Physiol Rev 95: 695–726, 2015
Published June 17, 2015; doi:10.1152/physrev.00024.2014
NEUROGLIAL TRANSMISSION
Vidar Gundersen, Jon Storm-Mathisen, and Linda Hildegard Bergersen
SN-Lab, Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, and
CMBN/SERTA/Healthy Brain Ageing Centre, University of Oslo, Oslo, Norway; Department of Neurology, Oslo
University Hospital-Rikshospitalet, Oslo, Norway; Center for Healthy Aging, Department of Neuroscience and
Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; and Brain and
Muscle Energy Group, Department of Oral Biology and Division of Anatomy, Department of Molecular Medicine,
University of Oslo, Oslo, Norway
Gundersen V, Storm-Mathisen J, Bergersen LH. Neuroglial Transmission. Physiol Rev 95:
695–726, 2015; Published June 17, 2015; doi:10.1152/physrev.00024.2014.—
Neuroglia, the “glue” that fills the space between neurons in the central nervous system,
takes active part in nerve cell signaling. Neuroglial cells, astroglia, oligodendroglia, and
microglia, are together about as numerous as neurons in the brain as a whole, and in
the cerebral cortex grey matter, but the proportion varies widely among brain regions. Glial volume,
however, is less than one-fifth of the tissue volume in grey matter. When stimulated by neurons or
other cells, neuroglial cells release gliotransmitters by exocytosis, similar to neurotransmitter
release from nerve endings, or by carrier-mediated transport or channel flux through the plasma
membrane. Gliotransmitters include the common neurotransmitters glutamate and GABA, the
nonstandard amino acid D-serine, the high-energy phosphate ATP, and L-lactate. The latter molecule is a “buffer” between glycolytic and oxidative metabolism as well as a signaling substance
recently shown to act on specific lactate receptors in the brain. Complementing neurotransmission
at a synapse, neuroglial transmission often implies diffusion of the transmitter over a longer
distance and concurs with the concept of volume transmission. Transmission from glia modulates
synaptic neurotransmission based on energetic and other local conditions in a volume of tissue
surrounding the individual synapse. Neuroglial transmission appears to contribute significantly to
brain functions such as memory, as well as to prevalent neuropathologies.
L
I.
II.
III.
IV.
V.
INTRODUCTION
ASTROGLIAL TRANSMISSION
OLIGODENDROGLIAL TRANSMISSION
MICROGLIAL TRANSMISSION
CONCLUSIONS
695
698
709
711
714
I. INTRODUCTION
Robustness against perturbations is important for the functioning of biological signaling networks (215). We posit
that gliotransmission contributes to making brain signaling
robust. There is an emerging understanding of how the
different types of glial cells interact with neurons to shape
the information processing in the mature healthy brain, as
well as of the importance for normal central nervous system
(CNS) development and contribution to disease processes.
These themes are the objectives of the present review.
The glia of the CNS was originally seen as “glue” keeping
the nerve cell elements together and involved in various
housekeeping functions. Rudolf Virchow (1821-1902),
“the father of cellular pathology,” called it “Nervenkitt”
and coined the term neuroglia in 1856 translating the German term into the Greek (192). [In singular, the words
neuroglia or glia refer to the supportive part of the nervous
tissue; in plural, the words refer to its cells (http://www.oed.
com/view/Entry/126393#eid34669799).]
It soon became evident that glia comprise three types of cell:
astrocytes/astroglia, microglia, and oligodendrocytes,
which were all ascribed special functions in the brain. Astrocytes were shown to play various housekeeping roles for
neurons, oligodendrocytes to make the myelin surrounding
axons, and microglia to be activated by diverse noxious
stimuli to the brain. In recent years, each of these types of
glia has been demonstrated to participate much more directly in the function of neurons than previously thought.
For a recent authoritative review on neuroglia, see the book
edited by Kettenmann and Ransom (190).
The term tripartite synapse was coined (12) to emphasize
the direct participation of astroglia in synaptic signaling,
along with the nerve ending and the postsynaptic part of the
neuron. Even tiny microglial processes contact synapses
(379), and oligodendroglia have neurotransmitter receptors
(186). In addition to direct participation in synaptic signal
transmission, through the release of “gliotransmitter,” neuroglia perform multiple nurture activities essential for normal nervous system function (such as providing nutrients
including energy substrates and transmitter precursors, re-
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GUNDERSEN ET AL.
moval of waste products). The proper control of these activities must rely on signal transmission, i.e., mutual exchange of information between neuron and glia, and on
interaction with the body through the bloodstream. Here
we review signaling to and from neuroglia, focusing on
signals mediated by the gliotransmitters glutamate, GABA,
ATP, D-serine, and L-lactate.
A. Neuroglia Numbers
The commonly held belief that neuroglial cells vastly outnumber neurons is misleading. In the grey matter of the
human neocortex, glia-to-neuron ratios are ⬃1.5 as determined by stereological methods using morphological identification of cell types (325, 373) or by isotropic fractionation combined with immunostaining for neuron-specific
nuclear antigen (NeuN) to distinguish neuronal and nonneuronal cells (16), the different methods giving similar
results. Subsequently, ratios ranging 1.3–2.7 have been reported for the grey matter of different regions of the human
cerebral cortex, highest in frontal and lowest in primary
visual (346). However, in subcortical white matter, glial
cells (mostly oligodendrocytes) vastly outnumber neurons
(not including passing axons) with a ratio of 15; in subcortical regions, the glia-to-neuron ratio may be as high as 10,
in cerebellum as low as 0.2 (because of the extremely large
number of granule cells), and in the brain as a whole ⬃1.
These figures are similar in human and non-human primates (16). The glia-to-neuron ratio increases roughly with
the size of the brain, along with a decrease in neuronal
density. It varies relatively uniformly with neuronal density
across brain regions (cortex, cerebellum, rest of brain) and
species of different mammalian orders (primates, scandentia, rodents, insectivores, cetaceans, marsupials, carnivore,
afrotherian) according to a power function [in the cerebral
cortex across several species, glia-to-neuron number ratio ⫽
(neurons per cubic mm)⫺1.256; r2 ⫽ 0.9, P ⬍ 0.0001] (162).
Interestingly, the average rate of use of glucose per neuron
does not vary with neuronal or neuroglial density (162). But
it presumably does vary with neuronal size (larger cells use
more glucose). Not only in white matter, but even in grey
matter of the human neocortex, oligodendrocytes are the
most numerous cell type, with the total number ranging
21–29 billion (109, female–male), while the total number of
astrocytes has been estimated to be in the range of ⬃5– 8
billion, microglia 1.8 –2.0, and neurons 21–26 (325). On
the other hand, nerve cell elements make up the greater part
of the volume of brain tissue. In the neuropil of the grey
matter of hippocampus CA1, for example, the glial contribution (mostly astrocyte processes) to the tissue volume was estimated at ⬃6% (274) or 4% (424) in rat, and
5% in human (154). The percentage of glial volume depends on the region and on the tissue preparation, but
rarely exceeds 20.
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B. Volume Transmission
The concept of volume transmission, as opposed to wired
transmission, matches neuroglial transmission. The concept
was introduced by Kjell Fuxe and Luigi Agnati and collaborators (3, 4, 130) to describe the fact that the action of
neurotransmitters is not confined to the synapse, because
the transmitter can diffuse out of the synaptic cleft to reach
receptors on cells at a distance from the site of release.
Moreover, transmitters, e.g., monoamines, are often released from axon varicosities that do not form synaptic
contacts, but activate receptors after diffusing for a variable
distance in the extracellular space. Similarly, transmitters
released from neuroglial cells spread through the extracellular space before interacting with receptors, although
groups of vesicles in astrocytes have been observed to cluster in front of receptor sites on neurons (30).
Receptors outside the synaptic cleft will be more easily accessible to volume transmission such as by transmitters released from neuroglia, compared with wired transmission
by neurotransmitters released into the synaptic cleft from
the presynaptic terminal. Interestingly, synaptic and extrasynaptic receptors may cause different responses (189,
265).
C. Astrocytes
Based on the Golgi stain or staining for glial fibrillary acidic
protein (GFAP), astrocytes are known as the “star-shaped”
cells in the brain. However, GFAP does not reach out to the
most delicate processes. When astrocytes were filled with
fluorescent dyes it was evident that they rather have a
“bushy” cubic appearance (48, 291), sending out several
small processes, some of which contact neurons at synapses
(perisynaptic processes) and some blood vessels (perivascular processes) (332) (FIGURE 1). Most synapses, the presynaptic nerve ending and the postsynaptic dendritic part of
the neuron, are tightly enwrapped by delicate astrocytic
processes (424). Astrocytes are known to occupy their
individual domains in the brain neuropil, i.e., each site in
the neuropil is served by a single astrocyte. This means
that there is very little overlap (⬃5%) between processes
of neighboring astrocytes (48, 291). It has been estimated
that an astrocyte occupies a volume of ⬃66,000 ␮m3 (48,
291). As there are ⬃213 synapses/100 ␮m3 brain tissue
(197), this volume comprises ⬃140,000 synapses. Thus
the domain organization of astrocytes may be important
for astrocytes as modulators of synaptic transmission.
These numerous perisynaptic processes are coupled in
series with the perivascular end feet processes, enabling
astrocytes to make channels connecting the synaptic environment with the bloodstream. Parallel channels are
formed by the extracellular space surrounding the astrocyte processes. In addition, the perivascular astrocyte
processes, the perivascular end feet, control transfer of
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FIGURE 1. Neuroglia. A–D: classical drawings. A and B: fibrous astrocytes in white matter
(A) and protoplasmic astrocytes with fine peripheral processes in grey matter (B) form perivascular end feet. Adult human cortex. [From Ramon y Cajal (344), with permission from Oxford
University Press.] C: shows oligodendrocyte.
[From Kettenmann et al. (191).] D: shows microglial cells. Drawing is from a Lucifer yellowfilled cell in a brain slice. [From Fröhlich et al.
(124), with permission from John Wiley and
Sons.] E: schematic drawing of neuroglial contacts. Glia make contact with neurons. Astrocytes send processes to synapses, as well as to
capillaries (red). Oligodendrocytes make myelin
(brown), which intimately surrounds neuronal axons. Microglial cells (gray) pervade the neuropil
and, like astrocytes, make contact with neuronal
synapses. (Drawing by Gunnar F. Lothe, Institute
of Basic Medical Sciences, University of Oslo,
Oslo, Norway.)
substances to and from the extracellular space at the
blood-brain interface.
D. Oligodendrocytes
Like astrocytes, oligodendrocytes extend many processes,
but instead of contacting synapses the oligodendrocyte processes contact and wrap around a stretch of axon, forming
the myelin sheath (FIGURE 1). The long myelinated tracts of
axons are particularly important in the human brain where
the large size of the brain requires fast conduction velocity
to allow widely spaced areas to communicate with a minimum of delay (439). The saltatory conduction of myelinated axons, by which the nerve impulse jumps from node to
node separated by the internodes formed by the myelinated
processes of oligodendrocytes, is therefore essential for the
cognitive abilities of the brain (120). Mature myelinating
oligodendrocytes are formed from oligodendrocyte precursor cells (OPCs), which can be identified by their expression
of the proteoglycan NG2 and are also called polydendrocytes due to their highly branched processes. OPCs are present also in the adult brain, constituting ⬃9 and ⬃3% of the
total cell counts in white and grey matter, respectively, and
are regulated by synaptic glutamatergic and GABAergic input (124). Like astrocytes, oligodendrocytes are able to respond to changes in the cellular and extracellular environment. By doing so, oligodendrocytes are shown to be highly
plastic; they can regulate myelin production according to
neuronal activity and regenerate distorted myelin in brain
diseases.
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GUNDERSEN ET AL.
E. Microglia
Microglia are the innate immune cells in the brain. In the
healthy brain they show a highly branched and ramified
morphology (FIGURE 1). Microglia get activated in response
to almost any type of brain damage. Once activated microglia are transformed into two major cell types. First, the
microglial morphology is changed into an amoeboid form.
Second, the amoeboid microglia become active phagocytes,
eating cellular debris.
Activated microglia can produce a large variety of cytokines, and they influence the fate of neurons by secreting
either pro- or anti-inflammatory mediators. The function of
microglia in the healthy brain is rather poorly understood.
In the healthy brain the processes of microglia are delicate
and highly ramified. The processes are moving in the neuropil in search of activating stimuli. Ramified microglia are
dubbed “resting,” and in contrast to activated microglia,
they do not express various types of surface proteins, such
as major histocompatibility complex proteins. Which types
of signals make the processes of microglia move is unclear.
Moreover, there is no clear understanding of the consequences of microglia-neuron contacts in the healthy brain.
Like astrocytes, the processes of each microglia appear to
survey a volume of brain tissue that is free of processes from
any other microglial cell, occupying distinct nonoverlapping territories in the brain (100, 191, 338).
II. ASTROGLIAL TRANSMISSION
A majority of brain scientists study the properties of neurons, but neurons comprise only half of the cells in the brain
(see sect. I). As noted above, until recently it was thought
that astrocyte cells played a relatively passive role in the
central nervous system. By modulating the content of the
extracellular space around synapses, astrocytes can interact
with neurons to the extent that this organization was
termed the “tripartite synapse” to emphasize the direct participation of astroglia in synaptic signaling, along with the
nerve ending and the postsynaptic part of the neuron. For
example, astrocytes are endowed with glutamate transporters, which can rapidly take up synaptically released glutamate, and thus contribute to inactivation of the postsynaptic glutamate response (406). Astrocytes also contain K⫹
channels that flux excess extracellular K⫹ into astrocytes,
keeping the K⫹ concentration low around synapses. This is
important for avoiding K⫹-induced depolarization of neurons. In the past few years, however, it has become increasingly clear that signaling between neurons and astrocytes
plays a crucial role both in the information processing that
the brain carries out, and in pathological conditions.
In this respect it is interesting that astrocytes seem to actively participate in synaptic plasticity (417) and memory
formation (151). Mice transplanted with human glial pro-
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genitor cells, which developed into mature astrocytes,
showed increased long-term potentiation and better performance on different memory tests compared with mice that
received murine glial progenitors (151). This suggests that
human compared with mouse astrocytes are more competent of supporting activity-dependent plasticity and memory formation and raises the intriguing question of whether
the difference in higher brain functions between human and
rodents can, in part, be ascribed to astrocytes and whether
neurons and astrocytes work side by side as equal partners
in higher cognitive functions.
A. Neurons Signal to Astrocytes
Astrocytes harbor a series of neurotransmitter receptors,
e.g., for glutamate and ATP. In the cerebellum, several lines
of evidence suggest that small processes of astroglia contain
distinct regions that can each interact with a few synapses.
These perisynaptic Bergmann glial processes are equipped
with the AMPA type of glutamate receptor (254, 355). Glutamate released at the parallel fiber-Purkinje cell synapse
can directly activate Bergmann glia AMPA receptors (254),
triggering local Ca2⫹ transients in microdomains of Bergmann glial processes (143). This signal pathway has been
shown to regulate cerebellar motor function (355). In the
cerebral cortex, astrocytes do not express AMPA receptors.
Instead, the NMDA type of glutamate receptor is thought to
convey synaptic signals to astrocytes (211). In the hippocampus, astrocytes can respond to neurotransmitters released during synaptic activity by activation of metabotropic glutamate and ATP receptors, which in turn produce
an increase in the intracellular Ca2⫹ concentration (79,
318, 328, 335). As in the cerebellum, in the hippocampus,
localized Ca2⫹ responses can be elicited in microdomains of
astrocytic processes by neuronal activity (93). Also, physiological sensory stimulation causes similar increases in intracellular astrocytic Ca2⫹ levels in different brain regions
(331, 368, 436). Thus astrocytes are positioned in the brain
neuropil to sense local synaptic activity and respond to this
by elevations in the intracellular Ca2⫹ concentration
(FIGURE 2). Such local responses can be modulated by
arousal via locus coeruleus activation and the ensuing
global norepinephrine release from noradrenergic nerve
endings onto astrocytic ␣1-adrenergic receptors, increasing
astrocytic Ca2⫹ signaling and thereby the gain of the astrocytic network, enabling the network to respond to local
neuronal activity (322). It has been suggested that the ability of astroglia to act as detector of coincidence between
arousal and local activity may contribute to sensory-specific
attention shifts (322).
B. Astrocytes Signal to Neurons
Astrocytes can release small signal molecules, gliotransmitters, upon elevation in the intracellular Ca2⫹ concentration,
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including in response to neuronal activity. The gliotransmitters comprise, e.g., glutamate, GABA, D-serine, and ATP
(11). There is a debate in the field about how gliotransmitters are released, as dealt with in the following paragraphs.
Most groups have found evidence for an exocytotic release
mechanism (11), while some groups have found that gliotransmitters are released from astrocytes through channels,
such as the Ca2⫹-dependent Cl⫺ channel bestrophin 1
(310), volume-regulated anion channels (194), connexin/
pannexin (270), or P2X purinergic receptors (102). In addition, lactate has been shown to be released from astrocytes, probably through monocarboxylate transporters
(245, 431).
1. Vesicular transporters
Results from many research groups suggest that gliotransmitter release from astrocytes takes place through regulated
exocytosis. For this to happen, astrocytes must contain vesicles (synaptic-like microvesicles, SLMVs), into which gliotransmitters can be packed and stored. Indeed, a vesicular
compartment consisting of small (⬍50 nm in diameter) and
clear vesicles containing glutamate and its vesicular transporters, the VGLUTs, or D-serine has been visualized in
astrocytes from the intact brain (33, 37, 253, 295, 296,
386) (FIGURE 2). Cultured astrocytes also contain small
(⬃30 – 40 nm) and clear vesicles, which can transport glutamate through VGLUTs (74, 253; see also Ref. 384), as
well as transporting D-serine (253). The molecular identity
of the vesicular D-serine transporter is not known.
Although functional live imaging studies have not directly
visualized vesicles, they suggest that glutamatergic vesicles
are present in astrocytes. From such studies in cultured
astrocytes, the size of the vesicles is estimated to vary between ⬃30 –50 nm (43) and ⬎300 nm (64, 248). Even
VGLUT-positive vesicles of several microns have been
found in brain slice astrocytes, but these are produced by
stimulating the astrocytes either mechanically or with high
glutamate concentrations (184, 326, 445), suggesting that
these vesicles are involved in release of gliotransmitters in
pathological conditions.
Moreover, localization studies have suggested that the three
vesicular glutamate transporters, VGLUT1, VGLUT2, and
VGLUT3, as well as the vesicular ATP transporter VNUT
are all present in astrocytes. In cultured astrocytes,
VGLUT1, VGLUT2, and/or VGLUT3 have been detected
by immunohistochemistry (10, 37, 43, 74, 204, 236, 250,
268, 283, 336, 384, 458) and by reverse transcription polymerase chain reaction (RT-PCR) (268). It has been proposed that cultured cells can express proteins that normally
are not expressed in cells in situ. This does not contradict
the presence of VGLUTs in astrocytes, as they have all been
found to be localized in acutely isolated astrocytes both at
the protein level (236, 268, 458) and the mRNA level (458).
In line with this are immunohistochemical results, showing
that VGLUT1, VGLUT2, and VGLUT3 are indeed located
within delicate perisynaptic astrocytic processes in the intact brain (33, 37, 123, 295, 296, 333, 458). Interestingly,
VGLUT3 has been shown to be upregulated in astrocytes
after focal cerebral ischemia (360). In addition to brain
astrocytes, retinal Müller cells have been shown to release
glutamate by exocytosis of VGLUT3 containing secretory
vesicles (229).
In discordance to the above-mentioned studies, some studies do not find VGLUTs in astrocytes. Using knockout controls for VGLUT1-3 antibodies, one confocal study concludes that none of the VGLUTs is present in astrocytes
(222). In our previous studies (295, 296), the VGLUT labeling in astrocytes was also controlled for by using
VGLUT1 and VGLUT3 knockout tissue. The reasons for
discrepancies between the results of the former and the
latter studies are obscure. The main difference between the
studies is that the first study used another source of
VGLUT1 antibodies than that used by us (while both studies used the same source of VGLUT3 antibodies). Second,
while Li et al. (222) used GFAP, S100␤, and GLT as astrocyte markers, we used glutamine synthetase. It should be
noted that we do observe a clear colocalization signal at the
confocal level between GLT and VGLUT1 (V. Gundersen
and L. Ormel, unpublished observation), which we interpret as partly being due to the fact that GLT is located in
neurons (26, 408) and their nerve terminals (129). Such
colocalization was not reported by Li et al. (222). Third, Li
et al. (222) detected VGLUT by analyzing the intensity of
the colocalization signal from VGLUTs and the astrocyte
marker, while Ormel and co-workers (295, 296) detected
VGLUT signals directly within astrocytic processes by analyzing several confocal planes, which spanned through the
entire processes of astrocytes.
Moreover, two studies using microarray analysis did not
detect RNA transcripts for VGLUTs in isolated astrocytes
from the mouse brain (51, 239). This is in contrast to three
previous studies detecting mRNA for VGLUTs in acutely
isolated astrocytes by RT-PCR (37, 80, 458). Whether these
differences are due to methodological differences, such as in
the purity of the isolated samples, or sensitivity of the detection method, is not clear.
2. Gliotransmitter exocytosis
The presence of VGLUT containing small synaptic-like vesicles is in line with the findings that astrocytes are capable of
releasing glutamate from a vesicular compartment by regulated exocytosis. However, it should be noted that, like the
vesicular release of glutamate, release through anion channels is Ca2⫹ dependent as shown for bestrophin 1 (209,
391) and VRACs (1). Thus demonstrating Ca2⫹-dependent
release of glutamate from astrocytes is not sufficient to conclude that astrocytes can release glutamate by exocytosis.
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Direct detection of glutamate released from astrocytes has
mostly been performed in cultured astrocytes. Many such
studies are consistent with a vesicular release mechanism of
glutamate (19, 35, 36, 37, 55, 56, 70, 98, 141, 166, 177,
185, 236, 250, 268, 319, 412, 446, 457, 458). These reports not only show that astrocytic glutamate release is
Ca2⫹ dependent, but demonstrate that the glutamate release is sensitive to inhibition of various parts of the exocytotic release machinery in astrocytes. For example, glutamate release was inhibited by the VGLUT inhibitors rose
bengal and trypan blue, the vesicular H⫹-ATPase inhibitor
bafilomycin A1, and SNARE protein cleavage by clostridium toxins. However, it has been suggested that because
cleavage of SNARE proteins could interfere with insertion
of plasma membrane proteins, through which glutamate
can be released (see below), the effect of clostridium toxins
on glutamate release does not necessarily reflect vesicular
release (148). Therefore, the effect of blocking VGLUTs
and the vesicular H⫹-ATPase is particularly important for
concluding that the astrocytic release of glutamate is exocytotic. Direct evidence of D-serine release from vesicles in
cultured astrocytes has been given (252).
In addition, to clear and small vesicles (see above), cultured
astrocytes contain dense-core vesicles (54, 343). Like glutamate, ATP has been shown to be released from cultured
astrocytes in a fashion compatible with exocytosis (19), but
unlike glutamate, the release takes place through dense-core
vesicles or lysosomes (70, 301, 307, 339, 425, 461). It
should be mentioned that glutamate has also been proposed
to be released from lysosomes (223), but that glutamate
release seems to be much more prominent from small vesicles (236). The ATP release from lysosomes was recently
reported to be mediated through the vesicular nucleotide
transporter, VNUT (301).
Release of ATP from astrocytes has been reported to modify
the activity of neurons and astrocytes in several brain regions (42, 142, 199).
3. Nonvesicular gliotransmitter release
Astrocytes possess other mechanisms of releasing gliotransmitters than exocytosis. These mainly comprise membrane
proteins, which can route gliotransmitters out of astrocytes.
Opening of the hemichannels and purinergic P2X7 receptors described below is not elicited by an increase in internal
Ca2⫹ (405, 451), suggesting that when Ca2⫹ levels rise in
the astrocyte these proteins do not mediate gliotransmitter
release. Opening of unopposed connexin 43 (Cx43) hemichannels in astrocytes can lead to efflux of glutamate (178,
451) and ATP (13, 73, 183, 387). Similar conclusions have
been drawn for pore-forming purinergic P2X7 receptors.
This receptor type can cause ATP (21, 388), glutamate
(102), and GABA (432) to permeate the plasma membranes
of astrocytes. There is conflicting data as to whether Cx43
hemichannels or P2X7 receptors are the main channels for
ATP release from astrocytes. For example, a comparative
study by Suadicani et al. (388) found that ATP was released
through P2X receptors and not through Cx43 hemichannels, while opposite results were found by Kang et al. (183).
It has been proposed that opening of Cx43 hemichannels
occurs only after strong membrane depolarization and that
Cx43 hemichannels are closed under resting conditions
(71). This suggests that Cx43 hemichannels are most important as a source of gliotransmitter release under pathological conditions when the astrocytes are depolarized.
Both Cx43 hemichannels and P2X7 receptors are likely to
mediate “bulk” efflux of cytosolic small molecular compounds, further suggesting that these ways of gliotransmitter release are more important in pathology than physiology.
FIGURE 2. Gliotransmitter release from astrocytes regulates synaptic activity. A: a small process of an astrocyte loaded with Texas red to
visualize the structure of the astrocyte and the Ca2⫹ indicator fluo4 showing small and local elevations in intracellular Ca2⫹ concentrations in a
microdomain of the process (arrow). [From Di Castro et al. (93), with permission from Nature Publishing Group.] B: electron micrograph of a
perisynaptic astrocytic process (ast), surrounding a presynaptic terminal (term) and a postsynaptic dendritic spine (sp), containing labeling for
glutamate (small gold particles, short arrows) and VGLUT1 (large gold particles, long arrows) over the same SLMV (higher magnification in the
inset). [From Bergersen et al. (33), with permission from Oxford University Press.] C: electron micrograph of a nerve terminal (Ter) containing
gold particles for NMDA receptor 2B (arrows) at the extrasynaptic plasma membrane facing an astrocytic process (ast), which contains SLMVs
(arrowheads, higher magnification in inset). [From Jourdain et al. (179), with permission from Nature Publishing Group.] D: evanescent wave
microscopy of cultured astrocytes showing that VGLUT1-GFP containing vesicles (green) fuse with the plasma membrane upon mGluR5
stimulation with DHPG. The vesicles were loaded with the fluorescent dye acridine orange (bright spots in inset 1). When the vesicles fuse with
the plasma membrane, there is a rapid and transient increase in fluorescent intensity (brighter spot in inset 2), before the dye diffuses away
(insets 3 and 4). The times are milliseconds before and after the application of DHPG. [From Bezzi et al. (37), with permission from Nature
Publishing Group.] E: schematic overview of the mechanisms leading to increase in Ca2⫹ and release of gliotransmitters in astrocytes, and the
effects of gliotransmitters on synaptic activity. Glutamate and ATP are synaptically released from presynaptic nerve terminals. They activate
metabotropic glutamate and ATP receptors on nearby astrocytic processes, or AMPA receptors on astroglia (as shown, e.g., in cerebellar
Bergmann glia). This receptor activation leads to mobilization of Ca2⫹ from endoplasmic reticulum (ER). Alternatively, Ca2⫹ can flux into
astrocytes from the extracellular fluid via P2X receptors or TPRA-1 channels. The evidence for external influx of Ca2⫹ is less solid than for release
from internal stores. Increase in the cytosolic Ca2⫹ concentration is a trigger for exocytotic release of gliotransmitters (e.g., glutamate, D-serine,
ATP) or channel-mediated release via bestrophin-1 and VRACs. Gliotransmitters can also be released through Ca2⫹-independent opening of
P2X7 ATP receptors or Cx43 hemichannels. When released, the gliotransmitters can act on receptors on the presynaptic nerve terminal, or
on postsynaptic dendrites.
700
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Adding to the complexity of channel mediated release of
gliotransmitters, some studies conclude that pannexin
channels are the dominant hemichannel type for ATP release from astroglia (172, 389). Another study suggests that
initial ATP activation of astrocytic P2X7 receptors triggers
subsequent release of ATP through both Cx43 and pannexin 1 (135). Moreover, pannexin 1 is located both in
–50 ms
astroglia and neurons (171), and it is unclear whether astroglial or neuronal pannexins contribute to regulation of
neuronal function.
Most of the release studies on Cx43 hemichannels, pannexins, and P2X7 receptors have been performed in cultured
astrocytes or in astrocytoma C6 cell lines. The role of these
150 ms
200 ms
300 ms
E
Ca2+
Cx43
P2X7-R
Glutamate/ATP
Glutamate
mGluR
TRPA-1
NMDA-R
ATP
A-R
NMDA-R
Nerve
terminal
ATP
D-serine
ER
Glutamate
P2Y1R
mGluR
Ca2+
AMPA-R
AMPA-R
NMDA-R
VRAC
NMDA-R
Glutamate/aspartate/
taurine/ glutamine
Glutamate/GABA
Bestrophin-1
P2XR
Astrocyte
Dendrite
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proteins in gliotransmitter release from astrocytes in the
intact brain is still elusive. However, by using a Cx43 hemichannel blocking peptide, evidence was found for a role
of unapposed Cx43 hemichannel function in the physiological task of memory consolidation (382), as well as in neuroprotection against spinal cord injury (290), epileptic excitability (453), and neonatal ischemia (83, 85). In the retina, the effect on neuronal survival of blocking Cx43
hemichannels during ischemia was largely due to a rescue of
endothelial cells (78). The Cx43 blocking peptides
(TATCx43L2 and peptide5) used in the above-mentioned
studies are selective for hemichannels, but whether they are
isoform selective for the Cx43 protein is not resolved (2, 84,
435). Other studies suggest that Cx43 is involved in development of different pathological conditions, such as cerebral ischemia (277, 278, 378) and chronic pain (63). However, as these studies used Cx43 knockout tissue, it is difficult to differentiate between an effect on unopposed
hemichannels or gap junctional Cx43.
There is strong evidence for astrocytic release of glutamate
through volume-regulated anion channels (VRAC), both
from astrocytes in culture and in situ (1, 157, 193, 233, 395,
433). Like vesicular glutamate release, glutamate release
through VRACs is regulated by the intracellular Ca2⫹ concentration (156, 267). The question is whether, for example, neuronal activity can induce sufficiently large osmotic
changes in astrocytes under physiological conditions to trigger glutamate release through VRACs. In this respect it is
interesting that ATP has been shown to potentiate swellinginduced release of glutamate from astrocytes (228, 266,
267). Hitherto, glutamate release via VRACs has convincingly been demonstrated to take place only under pathological conditions, such as in stroke (116, 460) and spreading
depression (23). However, in favor of a physiological role,
it has been shown that bradykinin could stimulate VRACmediated release of glutamate under conditions that did not
cause visible astrocyte swelling (232). This was demonstrated for mouse astrocytes in culture, while bradykinin
seems to trigger a vesicular release of glutamate from cultured rat astrocytes (177, 268, 313). Despite the fact that
most studies conclude that VRACs mediate astrocytic glutamate release, this is probably not a way to selectively
regulate glutamate release from astrocytes. Along with glutamate, several other amino acids, such as aspartate, taurine, and glutamine, are released via the VRACs (193, 395).
Under physiological conditions, glutamate and GABA
could be released via another anion channel, the Ca2⫹activated chloride channel bestrophin-1. First, it was shown
that bestrophin-1-mediated GABA release from Bergmann
glia underlies tonic inhibition in the cerebellum (218), and
that the degree of tonic inhibition in different brain regions
correlates with the concentration of GABA in astrocytes
(452). Then the same group showed that bestrophin-1
could induce release of glutamate from hippocampal astro-
702
cytes (444) and that this release led to slow inward NMDA
receptor currents in CA1 pyramidal neurons (150). Immunoelectron microscopy has revealed that bestrophin-1 is
present in distal perisynaptic processes of astrocytes (444).
However, bestrophin-1 is not selectively localized in astrocytes, as the protein has been found both in astroglia and
neurons in the hippocampus and the cerebellum by in situ
hybridization and immunocytochemistry (218). The role of
bestrophin-1 in neurons is not known.
Thus it seems that glutamate can be released from astrocytes by at least two different pathways under physiological
conditions: channel-mediated bestrophin-1 release and vesicular release. Whether these release mechanisms operate
simultaneously or under different physiological conditions,
and which of the pathways are most active, remains to be
investigated.
There are no reports on vesicular GABA release from astrocytes. Thus, based on the above-mentioned studies, the
main glial release of GABA in the brain seems to occur in the
cerebellum, and the mechanism is release through bestrophin-1 situated on Bergmann glia. However, the finding of
high levels of GABA specifically in Bergmann glia (452) is
not easily reconciled with previously published observations. Immunoperoxidase light microscopy for GABA has
shown almost exclusive neuronal staining and no clear sign
of labeling of the characteristic radial Bergmann glia in the
Purkinje and molecular layer in the cerebellum [see, e.g.,
Figure 1, B and D, in Ottersen et al. (297)]. This suggests
that the concentration of GABA in the Bergmann glial cells
is rather low. Previous immunogold studies of glutamate in
the cerebellum (380) and the hippocampus (46) have shown
that the concentration of glutamate is similar in Bergmann
glia and hippocampal astrocytes. The glutamate concentration in astroglia in these regions is ⬃20% of that in glutamatergic nerve terminals, suggesting an astroglial glutamate concentration of ⬃2 mM. Bestrophin-1 is a Cl⫺ channel that is permeable for anions with the following order of
permeability: NO3⫺ ⬎ I⫺ ⬎ Br⫺ ⬎ Cl⫺ (391). It has been
shown that it also fluxes the negatively charged amino acids
aspartate and glutamate, in addition to the neutral zwitterion GABA. The relative permeability for these amino acids
is lower than for Cl⫺ [glutamate ⬃0.5 (311), GABA ⬃0.3
(218), aspartate ⬃0.2 (340)], but of the same order of magnitude. Opening of bestrophin-1 in cerebellar Bergmann
glia should therefore lead to competitive efflux of all of
these amino acids, and most likely to a higher release of
glutamate than of GABA. The role of Bergmann glia-derived glutamate and aspartate for neuronal activity in the
cerebellum has not yet been addressed.
Some of the above-described complex and partly conflicting
results in the channel-mediated release of gliotransmitters
could be due to the fact that these are all large pores, permitting release of several small molecules, including amino
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NEUROGLIAL TRANSMISSION
acids. It is also important that there is a large overlap in the
specificity of pharmacological blockers of the different
channels. For example, hemichannel inhibitors block
VRACs, and vice versa (450). It should also be kept in mind
that some of the widely used VRAC antagonists can also
block other mechanisms involved in glutamate release from
astrocytes. 4-(2-Butyl-6,7-dichloro-2-cyclopentyl-indan-1on-5-yl)oxobutyric acid (DCPIB), the proposed selective
blocker of VRACs, was recently shown to block connexin
hemichannels and the glutamate transporter GLT (41).
Likewise, 5-nitro-2-(3-phenylpropylamino)benzoic acid
(NPPB) inhibits voltage-sensitive Ca2⫹ currents and intracellular Ca2⫹ stores (196). Moreover, NPPB blocks the intermediate-conductance Ca2⫹-activated K⫹ current (121)
and pannexin-1 channels (243). The molecular identity of
VRACs is still awaiting discovery. Such an identification
will allow in-depth studies of these channels, including genetic deletion experiments, thus bringing the VRAC field a
major step forward. Moreover, care should be taken when
interpreting data from experiments using niflumic acid,
which is used to block bestrophin-1 responses. This is because niflumic acid is not selective, but blocks other types of
channel, e.g., VRACs (e.g., Ref. 312). In arteries, niflumic
acid and NPPB inhibit constriction by a mechanism that is
independent of Cl⫺ channel blockade, possibly blocking
Ca2⫹-dependent contractile processes (188). When this is
said, the bestrophin-1-mediated glutamate and GABA release studies referred to above also used genetic knockdown
of bestrophin-1 to ascertain the selectivity of the release.
4. Gliotransmitter release regulates neuronal activity
An important question is whether vesicular gliotransmitter
release from astrocytes takes place in intact brain tissue and
whether this can influence neuronal signaling. Indeed, several reports have concluded that gliotransmitters released
from astrocytes can regulate synaptic activity and modulate
neuronal plasticity. In hippocampal slices there is evidence
that glutamate is released from astrocytes to enhance or
depress both excitatory and inhibitory synaptic activity in
nearby neurons (8, 93, 114, 117, 179, 182, 235, 279, 280,
281, 328, 329, 361, 433). Of particular interest is the study
by Di Castro et al. (93) showing that basal and “minimal”
synaptic transmission can be detected by astrocytes, which
respond by fast and highly local increases in Ca2⫹ concentrations in subdomains of astrocytic processes. This local
Ca2⫹ increase was translated into release of glutamate and
enhancement of synaptic transmission (93).
The ability of astrocytic glutamate to modulate synaptic
activity is not restricted to the hippocampus. In slices from
the olfactory bulb (202) and thalamus (314), glutamate
derived from astroglia has been shown to modulate synaptic plasticity.
Not only astrocytes that are a part of the tripartite synapse
can regulate synaptic activity. Astrocytes contacting axons
can also release glutamate, which in turn can broaden the
action potential and cause elevation in the intraterminal
Ca2⫹ concentration and increased synaptic activity (363).
In the somatosensory cortex, astrocytes can modulate cortical rhythms by regulating the activities of synaptic NMDA
and adenosine A1 receptors, leading to increased excitation
and inhibition, respectively (113). Interestingly, cannabinoid signaling also links astrocytic glutamate release and
synaptic functions. In the intact brain in vivo, selective activation of the cannabinoid receptor CB1R in astrocytes can
mediate astrocytic glutamate release and subsequent LTD
and impairments in working memory (149).
There is growing evidence that astrocytes in the intact hippocampus can also release D-serine, which can act on the
glycine site of NMDA receptors and can enhance glutamatergic synaptic plasticity, such as LTP (161, 375, 449). In
the hypothalamus, D-serine released from astrocytes can
induce LTP (304). Interestingly, astrocyte-derived D-serine
has been demonstrated to regulate somatosensory cortical
plasticity in vivo (396).
Like glutamate, ATP acts as an excitatory transmitter at
brain synapses. In addition to vesicular release from presynaptic nerve terminals (212), ATP is released from astrocytes
and is proposed to regulate astrocyte networks by mediating propagation of Ca2⫹ waves between gap junction-coupled astrocytes (198). However, astrocytic ATP can also
regulate neuronal activity (199). Using hippocampal slices,
Pascual et al. (315) showed that ATP released from astrocytes was rapidly converted to adenosine, which produced a
tonic suppression of synaptic activity mediated by A1 adenosine receptors. Likewise, ATP gliotransmission is important for sleep homeostasis through production of adenosine
(146). The depressive effect of purines on synaptic activity
was shown to be caused by downregulation of neuronal
NMDA receptors, probably through an action on presynaptic A1 receptors (90). Adding to the data showing a physiological role of astrocytic ATP is the recent finding that
freshly isolated and in situ cortical astrocytes can release
ATP, which acts mainly on postsynaptic P2X7 ATP receptors to produce a reduction in dendritic GABAA receptors
resulting in downregulation of phasic and tonic inhibition
(210). In line with this study is the report (305) that astrocytes in the hippocampus can detect physiological synaptic
activity (“minimal synaptic stimulation”) by local increases
in intracellular Ca2⫹. This leads to release of purines that
can regulate synaptic transmission through presynaptic A2
purinoceptors. Interestingly, adding to the growing evidence for the role of astrocytes in complex brain functions,
astrocytes in the brain stem have been demonstrated to act
as chemosensors (142). They respond to changes in pH by
elevations in intracellular Ca2⫹, causing ATP release, which
in turn activates chemoreceptor neurons, leading to increased breathing (142).
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In all of the above-mentioned studies the release of gliotransmitters is dependent on a rise in the intracellular Ca2⫹
concentration in astrocytes. The release mechanism of gliotransmitters has been addressed in detail in some of the
studies, among others by determining the sensitivity to
blocking SNARE proteins. Functional methods, including
patch-clamp electrophysiology, have produced substantial
evidence for exocytosis of glutamate from astrocytes in intact tissue (114, 179, 329). Also the release of D-serine from
hippocampal astrocytes seems to follow an exocytotic route
(161). This is also true for ATP release from the hippocampus and the cerebral cortex (146, 211, 315). In contrast,
there is also evidence that volume-regulated anion channels
mediate efflux of glutamate from hippocampal astrocytes
(433).
From the above discussion it is clear that gliotransmitter
release is regulated by various mechanisms and can lead to
a wide variety of synaptic responses. Glutamate from astrocytes can enhance synaptic strength by stimulating metabotropic or NMDA type glutamate receptors on presynaptic
nerve terminals, causing increased synaptic release of glutamate (117, 179, 329). At inhibitory synapses a similar
mechanism seems to enhance GABAergic inhibition; synaptically released GABA stimulates astrocytes to release glutamate, which then acts on presynaptic GABA terminals to
increase GABA release (182). In addition, astrocytic glutamate release can increase neuronal excitability by stimulating NMDA receptors located outside the synaptic specialization on postsynaptic dendrites (9, 77, 114, 314, 328).
This generates slow inward synaptic currents (SICs)
through the NMDA receptors, which can contribute regulation of excitability in a large network of neurons. Bear in
mind that one astrocyte “overlooks” as many as 14,000
synapses (see sect. I).
These different actions of one single gliotransmitter, such as
glutamate, could be related to the brain regions in which it
is released. For example, enhancement of synaptic strength
is observed in the dentate gyrus, while SICs are mostly
found in the stratum radiatum of the hippocampus proper.
Also the nature of the intracellular Ca2⫹ signal in the astrocytes is important for the release probability of gliotransmitters from astrocytes. This is exemplified by the fact that
activation of different receptors on astrocytes results in various types of intracellular Ca2⫹ signals. All of these are not
equally capable of stimulating gliotransmitter release, as
observed in hippocampal slices, where Ca2⫹ elevations triggered by activation of PAR-1 receptors, but not P2Y1 receptors, elicit NMDA receptor mediated SICs (374). In this
respect, it is likely that local Ca2⫹ elevations in microdomains of astrocytic processes, which contact synapses,
modulate the probability of gliotransmitter release, and
thus the effect on synaptic function (426). So far, three
studies (93, 143, 305) have addressed the question of local
Ca2⫹ increases in astrocytic processes, all emphasizing that
704
most of the astrocytic Ca2⫹ activity leading to astrocytedriven alteration of synaptic function occurs in the tiny
processes, not in the cell soma (426). It should be mentioned
that most studies have concluded that elevations in the cytosolic Ca2⫹ concentrations in astrocytes are caused by activation of metabotropic G protein-coupled receptors and
inositol 1,4,5-trisphosphate (IP3)-dependent mobilization
of Ca2⫹ from internal stores, such as the endoplasmic reticulum (426). However, influx of Ca2⫹ from the extracellular
fluid through transient receptor potential ion 1 (TRPA1)
channels (375) or P2X1/5 and P2X7 receptors (294, 303)
could contribute to the rise in the intracellular Ca2⫹ concentration in astrocytes.
Di Castro, Panatier, and co-workers (93, 305) show that
activation of only a few synapses can trigger small and local
increases in astrocytic Ca2⫹ levels, which in turn lead to
enhanced synaptic transmission, but there are some differences between these studies. First, the results of Di Castro et
al. (93) [along with those reported in Jourdain et al. (179)]
suggest that glutamate is the transmitter released from astrocytes, acting on presynaptic NMDA receptors. In contrast, Panatier et al. (305) show that astrocytes release purines, which in turn stimulate presynaptic adenosine A2
receptors. Second, Di Castro et al. (93) suggest that activation of P2Y1 ATP receptors elicits Ca2⫹ increase in microdomains of the astrocyte, while Panatier et al. (305)
suggest that the astrocytes are activated by mGluR5. These
differences could be explained by the fact that the former
studies were performed in the dentate gyrus, while the latter
used the CA1 region of the hippocampus as a model system.
Thus astrocytes in different brain regions could be equipped
with different densities of various types of receptor along
their processes, and they could use different gliotransmitters to modulate synaptic transmission. The source of the
ATP that stimulates astrocytes in the dentate gyrus was not
resolved in Di Castro et al. (93). If ATP is released from
astrocytes, this would speak against the possibility that the
observed Ca2⫹ events in astrocytes are a direct consequence
of synaptic activity, but it should be kept in mind that ATP
is indeed released at glutamatergic synapses in the brain
(212, 307a).
Further contributing to a substantial complexity of the action of gliotransmitters on the neuron-glia network activity
is the fact that a single gliotransmitter can have different
effects depending on the neuronal element and which receptor subtypes it reaches. For example, glutamate released
from astrocytes may cause different effects, depending on
whether it interacts with synaptic or extrasynaptic receptors (189), the latter presumably being more easily accessible to astrocyte-derived glutamate. Whereas activation of
synaptic NMDA receptors has neuroprotective effects, activation of extrasynaptic NMDA receptors causes neuronal
damage via increased neuronal NO and the ensuing nitrosative stress leading to synaptic damage and other mecha-
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NEUROGLIAL TRANSMISSION
nisms (265). While the physiological significance of this
response remains to be determined, it may help explain the
deleterious effect of amyloid-␤ peptide (A␤) on synapses in
Alzheimer’s disease: oligomeric (but not monomeric) A␤
binds to and stimulates ␣7 nicotinic acetylcholine receptors
on astrocytes, which in turn leads to release of glutamate.
This astrocytic glutamate activates extrasynaptic NMDA
receptors to depress excitatory synapses in hippocampus
(397). This action of A␤ was blocked by the novel, extrasynaptic-selective NMDA receptor antagonist nitromemantine (397), providing promise for treatment, and illustrating the importance of neuroglial transmission.
Another interesting possibility is that molecular heterogeneity of astrocytes can contribute to explaining the different
results on mechanisms underlying gliotransmitter release
described above. Astrocytes have generally been thought to
make up a rather homogeneous population of cells, because
they all have similar “passive” electrophysiological properties. However, it is known that astrocytes in the grey matter
of different brain regions display different morphologies
(106), indicating that these populations have different molecular compositions. Such a phenomenon was first detected in mouse hippocampus, where GFAP expressing astrocytes were divided into seemingly nonoverlapping
groups containing either glutamate transporters or AMPAtype ionotrophic glutamate receptors (255). However, later
the “AMPA type” of astrocyte has been identified as OPCs
(414). In human isocortical and hippocampal astrocytes,
the plasmalemmal protein and extracellular matrix receptor
CD44 is a marker of astrocytes with “fibrous” as opposed
to “protoplasmic” morphology, and is correlated with high
immunostaining for GFAP, and S100␤, but low immunostaining for glutamine synthetase, and excitatory amino
acid transporter 1 (EAAT1), and EAAT2 (381). As discussed above, astrocytes can perform a wide variety of functions. However, whether these diverse functions can be performed by all astrocytes, or are attributes of distinct subpopulations, remains an open question. Only a few
experimental approaches have been used to dissect the molecular diversity of astrocytes, e.g., Doyle et al. (101) used a
novel RNA detection system (TRAP, BAC transgenic mice,
see below) to show that astrocytes isolated from the cortex
and the cerebellum have different mRNA sets. However,
these studies did not investigate mRNA profiles of astrocytes from several brain regions. Gene expression profiles
of astrocytes have been presented (51, 240). While reporting the transcriptome of the whole astrocyte population, these studies did not provide any additional insight
into their heterogeneity. Methodological limitations prevent the accurate determination of the astrocytic transcriptome (327).
5. L-Lactate: transmitter and fuel
Astrocytes are not only sources of release of “classical”
gliotransmitters; they can also produce and release lactate,
for which there is growing evidence of an action as a volume
transmitter in the brain (29). Astroglia make lactate by
glycolysis from astrocyte-stored glycogen or from bloodborne glucose. Lactate diffuses down its concentration gradient 1) intracellularly, 2) through the gap junction connected astrocytic network, 3) into the extracellular space
through MCTs, 4) extracellularly along glial and neuronal
processes, and 5) into adjacent neurons and other cells via
MCTs. Through these routes (FIGURE 3), astrocyte-derived
lactate may act as an autocrine mediator on receptors on
astrocytes, or as a paracrine mediator on receptors on neurons and other cells at a distance, i.e., as a volume transmitter (29). Similarly, lactate released from neurons could act
on lactate receptors on glia as well as neurons. The notion
that lactate can travel considerable distances in brain tissue
from a point of release is supported by observations on the
distribution of microinjected radiolabeled lactate and inulin
(75). As expected, inulin, which is restricted to the extracellular space, spread farther than lactate, which accesses intracellular compartments and is metabolized (1.5 and 2.4
mm, respectively, in 10 min). When lactate is produced
from glucose, proton is generated corresponding to the production of lactic acid (271), which is dissociated to a proton
and a lactate anion at physiological pH. The MCTs cotransport lactate with protons, in a facilitative transport process
driven by the concentration gradients of protons and lactate
(147). Changes in pH that accompany lactate transients
may therefore cause effects in addition to those of the lactate anion. pH is known to affect a wide range of ion channels and receptors (438), including glutamate receptors
(246, 410). pH even modifies (and is modified by) histone
acetylation, thereby influencing gene expression (258). Lactate is formed from pyruvate through the lactate dehydrogenase reaction, regenerating NAD⫹ to sustain glycolysis,
and can undergo the reverse reaction to produce pyruvate
and change the NADH-to-NAD⫹ ratio. The extracellular
lactate-to-pyruvate ratio reflects the intracellular NADHto-NAD⫹ ratio, although this relation will be perturbed on
deviation from equilibrium conditions (390). Pyruvate as
well as redox change can signal through gene control (276),
e.g., modifying protein deacetylation by sirtuins (62, 342).
The NADH-to-NAD⫹ ratio also has signaling effects at the
protein level. Thus lactate, through increasing the NADHto-NAD⫹ ratio, augments NMDA receptor function, increasing intracellular Ca2⫹ levels and thereby stimulating
the expression of synaptic plasticity-related genes both in
vitro and in vivo (447). The redox ratio and the lactateto-pyruvate ratio form a signaling network (61, 155,
263) contributing to the volume transmitter actions of
lactate (29).
Recently, a lactate receptor in the strict sense was discovered to be active in the brain (31, 45, 213), namely, the G
protein-coupled receptor GPR81, also known as hydroxycarboxylic acid receptor 1 (HCA1 or HCAR1). GPR81 was
“deorphanized” by being shown to cause downregulation
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GUNDERSEN ET AL.
A
T
T
A
S
A
S
t
s
F
Lactate
Glucose
GLUT3
Glucose
MCT
Lactate
Lactate
HCAR1
GLUT1
Glycogen
Axon
terminal
HCAR1
Lactate
Cx
mGluR
Lactate
Astrocytes
MCT2
Spine
AMPA-R
FIGURE 3. Lactate signaling in neuroglia.
A: electron micrograph showing double immunogold labeling at synapses between
parallel fiber terminals (T) and Purkinje cell
spines (S). The section was double-labeled
with antibodies to GluR2/3 (15-nm gold
particles) and to MCT2 (10-nm gold particles). [From Bergersen et al. (32), with permission from Oxford University Press.] B:
the membranes of the Bergmann glia facing the parallel fiber terminals and Purkinje
cell spines are labeled with antibody to
MCT4 (10-nm gold particles). [Modified
from Bergersen (27), with permission from
Oxford University Press.] C: the lactate receptor (10-nm gold, red arrowheads) is at
the postsynaptic membrane (black arrowheads). Synapse of a nerve terminal (t) and
a dendritic spine (s) is shown. Stratum radiatum, hippocampus CA1. [Modified from
Lauritzen et al. (213), with permission
from Oxford University Press.] D and E: the
lactate receptor GPR81/HCAR1 (green) is
in the pyramidal cell somatodendritic compartment including spines (white arrows in
D). Hippocampus CA1. Neurons labeled for
MAP2 (red), nuclei with DAPI (blue).
[Adapted from Bergersen (28), with permission from Nature Publishing Group.] F:
schematic representation of L-lactate production and action at the “tripartite synapse” (see text). (For simplification, pyruvate and other intermediates are not
shown.)
MCT4
MCT1
HCAR1
Glucose
Lactate
Mitochondrion
GLUT3
Spine neck
Dendrite
706
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of cAMP in adipocytes (53, 231) in response to insulininduced lactate production, the released lactate acting as an
autocrine messenger mediating the antilipolytic action of
insulin (5). HCAR1 has millimolar affinity for L-lactate, the
EC50 ranging 1–7 mM depending on the assay conditions
and the species, and unlike lactate transporters and metabolizing enzymes, has similar affinities for L-lactate (the physiological enantiomer) and D-lactate. The receptor is highly
selective for lactate compared with other short-chain fatty
acids. In the brain, the extracellular concentration of L-lactate as measured by microdialysis is ⬃1 mM at rest, and
when lactate was infused intravenously to reach a blood
concentration of ⬃10 mM, the extracellular concentration
in the brain was ⬃2 mM (152). These concentrations are in
the dynamic range of the receptor. Importantly, at lactate
concentrations below the EC50, the effect on the receptor is
roughly proportional to the concentration. Agonists with
higher affinities and high selectivity towards HCAR1, compared with HCAR2, HCAR3, and other closely related receptors, have been identified, including 3,5-dihydroxybenzoic acid (apparent EC50 ⬃0.15 mM) (230), its derivative
3-chloro-5-hydroxy benzoic acid (apparent EC50 ⬃0.02
mM) (104), and the high-affinity “Compound 2,” 4-methyl-N-(5-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-4-(2-thienyl)-1,3-thiazol-2-yl)cyclohexanecarboxamide (apparent
EC50 ⬃0.00005 mM) (357). The availability of high-affinity ligands will facilitate investigations of the physiological
and pathophysiological roles of HCAR1 and serve as a
basis for developing potentially useful drugs. The fact that
hydroxyphenolic acids are constituents of foods, such as
vegetables, fruits, and berries, and may activate HCAR1
more strongly than lactate, suggests that natural products
from foods could modify lactate receptor transmission.
Natural transient changes in the brain extracellular lactate
concentration occur during physical exercise (87, 300, 409,
419). The discovery of the lactate receptor in brain invites
the hypothesis that intermittent HCAR1 activation mediates some of the beneficial effects of physical exercise on the
brain by modifying lactate gliotransmission. The hypotheses that the lactate receptor contributes to effects of nutrients and physical activity on the brain should be tested
experimentally.
In rat hippocampus slices, the lactate receptor downregulates forskolin-stimulated cAMP (213), and in primary cultures of mouse cortex, it downregulates Ca2⫹ spiking activity in principal neurons as well as in GABAergic neurons
(45). These observations indicate that receptor action of
lactate can curb excessive neuronal activity, e.g., in a situation of stress where excessive adrenoceptor activation of
neurons with ensuing excessive cAMP leading to leaky ryanodine receptors (237) or overstimulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) and
KCNQ potassium channels (316, 434) with consequent
cognitive dysfunction, could be tempered by lactate produced in response to adrenoceptor activation of astrocytes
to produce lactate acting on HCAR1. This is still a hypothesis awaiting testing.
In contrast to such negative regulation, lactate has recently
been proposed to mediate positive feedback regulation of
norepinephrine release from locus coeruleus neurons: astrocyte delivered lactate caused upregulation of cAMP in these
neurons, with relatively high affinity (apparent EC50 ⬃0.5
mM) and stereospecificity (398) compared with HCAR1.
The authors (who did not seem to be aware of the previous
work on brain lactate receptors) concluded that the effect
must be mediated by a lactate receptor other than HCAR1,
due to the higher affinity, different substrate specificity, and
opposite effect on cAMP. However, as G protein-coupled
receptors act with ligand-dependent bias through variable
intracellular messenger systems (345), the action might still
involve HCAR1. Recently, HCAR1 has been shown to signal, independently of adenylyl cyclase, through arrestin-␤2,
inhibiting tissue damage via innate inflammatatory mechanisms involving Toll-like receptors and the nucleotide binding and oligomerization domain-like receptor family pyrin
domain containing 3 (nod-like receptor protein 3, NLRP3)
inflammasome (168), and through a protein kinase C
(PKC)-dependent pathway and an IGF-IR transactivationdependent pathway to activate ERK1/2 (224), demonstrating that the result of GPR81/HCAR1 activation is not limited to inhibition of adenylyl cyclase. The effects of lactate
through inflammasome inhibition prevented death from experimental hepatitis and pancreatitis (168), indicating a significant therapeutic potential. These effects were observed
after administering lactate intermittently to obtain blood
concentrations comparable to those occurring after bouts
of moderate to intense physical exercise, suggesting relevance for life-style intervention. Toll-like receptors have
complex roles in brain and are implicated in Alzheimer’s
disease (AD) (413). Of note, the NLRP3 inflammasome is
activated in human mild cognitive impairment and contributes to neuropathology in AD (139, 160, 234). The possibility of intervention in these disease mechanisms through
the lactate receptor opens a new field of research.
As the only cell in the CNS that contains large amounts of
glycogen (330), astrocytes provide an obvious source of
lactate. According to the astrocyte-to-neuron lactate shuttle
(ANLS) hypothesis, lactate produced by glycolysis, triggered in astrocytes to provide energy for taking up transmitter glutamate from active synapses, is shuttled over to
the active neurons (review in Ref. 324). Neurons may depend on this lactate for synaptic transmission (nucleus of
the solitary tract, Ref. 275) and for essential functions such
as memory formation (393). Another observation indicating the involvement of lactate in synaptic plasticity is that
the lactate transporter MCT2 as well as postsynaptic density 95 (PSD95) protein and glutamate receptor subunit 2
(GluR2) are enhanced by the synaptic plasticity mediator
brain-derived neurotrophic factor (BDNF) (350).
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The ANLS hypothesis is still controversial (reviews in Refs.
94, 97). A contrasting view is that direct uptake of glucose
into neurons is substantial both at rest and in activation and
that neuronal glucose-derived pyruvate rather than astrocyte-derived lactate is the major oxidative fuel in neurons
(321). Astrocytes account for ⬃30% of the brain oxidative
rate (163), which exceeds (274), although thought similar
to (163), their proportion of the brain volume, indicating at
least as high oxidative rates in astrocytes as in neurons.
Furthermore, it has been asserted that astrocytes have faster
and higher capacity for lactate uptake and dispersal via the
astrocytic gap junctional syncytium, compared with shuttling of lactate to neurons from neighboring astrocytes, and
can also deliver glucose to neurons (133). Astrocyte mitochondria are retained at sites of intense glutamate uptake
induced by neuronal activity, as recently shown in slice
cultures of rat hippocampus (175), supporting the role of
oxidative metabolism in astrocytes to provide energy for
their Na⫹-K⫹-ATPase. In a review, Hertz et al. (163) point
out that astrocytes, because of their content of pyruvate
carboxylase, can synthesize glutamate (which can be released as gliotransmitter, or funneled to neurons as glutamine). They also point out that astrocytes oxidize glutamate. An advantage of using oxidation of glutamate to
fuel glutamate uptake is that substrate is available according to demand and that it spares glucose for use by
neurons (96).
The thinnest processes of astrocytes, which enwrap other
cells and constitute most of the astrocytes’ surface area,
have no mitochondria, but do contain glycogen; they depend on glycogenolysis and glycolysis, or intracellular diffusion of high-energy phosphate compounds for energy
supply. Mitochondria have been described at branching
points of peripheral astrocytic processes (214), but the pictures (Figure 7 of Ref. 214) show that mitochondria do not
occur in the fine juxtasynaptic processes, which are too
narrow for larger organelles. The glycolysis in mitochondria-less but glycogen-laden perisynaptic astroglial processes will increase intracellular as well as extracellular lactate levels (lactate exiting through MCTs). However, activated neurons may produce lactate from ambient glucose
without glycogenolysis, as illustrated by climbing fiber
stimulation of AMPA-type glutamate receptors on cerebellar Purkinje cells. This caused increases in extracellular lactate, postsynaptic currents, blood flow, and glucose and
oxygen consumption, which were blocked by blocking
AMPA receptors with CNQX, but not by blocking glycogenolysis (50). This observation indicates that lactate exits
the activated neurons, rather than entering neurons from
astocytes. As the lactate concentration in the dialysate rose
by 30% during stimulation (50), considerable local lactate
concentration transients must be expected in brain tissue
during neuronal activity, providing a basis for dynamic activation of lactate receptors such as HCAR1.
708
Interestingly, the transient lactate increase in cortex in response to visual stimulation is significantly greater in panic
disorder patients compared with controls (244), perhaps
indicating that the long-known ability of sodium lactate
infusion to provoke panic attacks in susceptible individuals
involves an action on lactate receptors. Panic disorder patients have ␤-adrenoceptors with lowered affinity (217) and
low cAMP levels (251) (both recorded in blood cells, as
proxy for brain), suggesting that cAMP may be disproportionately reduced on activation of HCAR1 by lactate.
Whereas most of the energy consumption in synaptic transmission goes to driving postsynaptic currents (15, 153), the
spines generally lack mitochondria (226, 330). Consistent
with this, the complex of glycolytic enzymes is associated
with the plasmalemma and endoplasmic reticulum membranes, and ATPases transporting K⫹, Na⫹, and Ca2⫹ use
ATP from glycolysis (92). This means that lactate produced
in glycolysis must diffuse through the spine neck to the
dendrite branch to be oxidized in mitochondria there, or
exit the spine through MCT2, conveniently situated at the
PSD (32), to be oxidized in other cells. Alternatively, lactate
may reenter the spine later, if the concentration gradient
reverts upon mitochondrial oxidation, and then diffuse to
reach mitochondria in the dendritic branch proximal to the
spine. The time required for diffusion of lactate to reach
mitochondria may help explain why glucose consumption
exceeds oxygen consumption shortly after brain activation
(95). It will be interesting to work out the time-lag represented by such translocation of lactate compared with the
lag in oxygen consumption. Generation of lactate in the
tissue is implicated in the concomitant increase in blood
flow (418). Interestingly, this increase in blood flow without
an increase in oxygen consumption is dependent on ␤2adrenergic receptors and abolished by ␤-adrenoceptor
blockers (341, 366). These observations may represent
arousal-triggered ␤-adrenoceptor stimulation of cAMP, enhancing glycolysis (220). Part of this glycolysis in excess of
oxidation would occur in the activated dendritic spines
(50), which on activation could form a microdomain of
high lactate concentration.
The lactate receptor HCAR1, colocalized with MCT2 at the
synaptic spine, and to a lesser extent also on vascular endothelium and astroglia (213), could be activated by the exiting lactate to curb cAMP. As cAMP stimulates glycolysis in
brain (220), this would serve to prevent excessive rates of
glycolysis in the spine, one effect of which would be excessive decrease in pH. Low pH is known to inhibit glutamate
receptors (247, 273, 410) and affect excitability by modifying Cl⫺ channels (323). In astrocytes, high pH causes
increased production of cAMP by bicarbonate-sensitive soluble adenylyl cyclase-activated by bicarbonate taken up
through the electrogenic NaHCO3 cotransporter (NBC) after elevation of extracellular potassium, in response to local
neural activity, leading to glycolysis with production of lac-
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tic acid (67). In addition to counteracting the alkalinization
caused by bicarbonate uptake, the ensuing lactate release
from astrocytes could act as a gliotransmitter on glial and
neuronal HCAR1 to downregulate the elevated cAMP and
stabilize pH.
Several observations indicate neuroprotective effects of lactate in conditions such as brain ischemia or brain trauma
(40, 76, 369, 370). After traumatic cerebral injury, the
brain appears to switch from glucose to lactate as a the main
fuel (138). However, the beneficial effects of lactate are not
fully accounted for by metabolism (97); for instance, lactate
cannot cause energy production in the absence of oxygen. It
now appears probable that actions via the lactate receptor
HCAR1 explain these effects, at least in part, as well as
resolving controversies over the ANLS hypothesis.
Extracellular lactate, originating in excitatory synapses on
spines, or in astrocytic processes, would be able to activate
HCAR1 and possibly other lactate receptors, on the spines,
or on other structures in the brain tissue, exemplifying volume transmission to and from astrocytes. The selective localization of the lactate transporter MCT2 (32) as well as
the lactate receptor HCAR1 (213) at the postsynaptic membrane, and in intracellular compartments, of glutamatergic
synaptic spines (FIGURE 3) suggests that lactate forms a hub
where synaptic transmission and neuroglial transmission
meet.
An example of probable involvement of lactate in such neuron-glia interaction is through BDNF, a factor essential for
neural plasticity and learning (216), and for the beneficial
effects of physical exercise on the brain (66, 112, 420).
BDNF is thought to exert autocrine/paracrine action (22,
170) on neurons and is produced by neuronal cells as well as
astrocytes in response to stimulation by lactate (69). Moreover, intravenous infusion of lactate causes BDNF to increase in blood, probably originating in brain (365). The
mechanism of this stimulatory effect of lactate on BDNF
remains to be determined, one possibility being that
HCAR1 is involved. In exercise, the lactate receptor on
neurons and glia could be activated by lactate entering from
blood and/or produced by astrocytes in response to catecholamines as outlined below.
In section IIA, we mentioned that the global activation of
astrocytes, triggered in arousal through noradrenergic axons from locus coeruleus hitting ␣1-adrenergic receptors on
astrocytes to increase Ca2⫹ signaling in the astroglial network, enhances responses to local neural activity (322). In
parallel, the norepinephrine released will also activate ␤2adrenergic receptors to increase cAMP and augment glycolysis, powering, inter alia, membrane transport essential for
neuronal and glial signaling (see above) (92). Increased astrocytic cAMP will also favor the open mode of gap junctions (108), thereby augmenting spread of solutes, such as
lactate, for signaling and support through the astrocytic
network. These complementary components of arousal
combine to prepare the brain for action. It is intriguing that
gliotransmitter lactate from locus coeruleus astrocytes is
one of the agents that can elicit the increased locus coeruleus activity to cause general arousal (398). The subsequent release of gliotransmitter lactate from regional astrocytes in response to elevated cAMP provides a feedback
mechanism through HCAR1 to prevent excessive and longlasting rise of cAMP and to tune the cAMP level to fit local
and immediate needs. It is becoming increasingly clear that
the cellular level of cAMP has an optimum, the apex of the
bell-shaped dose-response relationship, that may vary depending on the cell and the conditions (14). Thus cAMP can
have both positive and negative effects in cell physiology
and survival (174). High cAMP can enhance perception in
sensory cortex (322) and enhance memory and antidepressant-like effects in the prefrontal cortex (437), but can impair prefrontal cortex networking required for working
memory and higher cognitive functions such as abstract
thought and working memory through excessive opening of
HCN potassium channels, which are colocalized with
cAMP-related proteins in spines at glutamatergic synapses
(316, 434), where also HCAR1 is concentrated (FIGURE 3).
The observation (352, 441) that high-impact exercise
(blood lactate ⬎10 mM) improves memory may be seen in
this context: lactate from blood, as well as from astrocytes
stimulated by the elevated catecholamines (see above),
could act through HCAR1 on spines to temper excessive
cAMP levels. cAMP control mechanisms enable flexible
modulation of network strength, but when dysregulated,
may result in mental disorders, including schizophrenia,
bipolar disorder, autism, and age- or stress-dependent cognitive impairment (105, 132), and even neurodegeneration
such as in AD (59). Lactate gliotransmitter signaling via
HCAR1, with its widespread distribution in brain regions
and in neurons as well as glia (213), is positioned to contribute to optimizing the local cAMP concentration. It is
now important to provide experimental evidence clarifying
the extent to which HCAR1 activity contributes to cAMP
optimization in different physiological and pathophysiological conditions.
III. OLIGODENDROGLIAL TRANSMISSION
A. Glutamate and GABA
Another novel realm of transmitter action is brain white
matter. Fast impulse conduction through white matter
tracts is a prerequisite for rapid interactions between spatially separated brain modules and is required to perform
higher brain functions. Therefore, the myelination and sustenance of long axons by oligodendrocytes can be assumed
to be carefully regulated. Indeed, evidence is accumulating
that the action of neuronally released neurotransmitter substances is not limited to astrocytes and microglia (see be-
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GUNDERSEN ET AL.
low), but also contributes to the interplay between neurons
and oligodendroglia. Indeed, receptors for various neurotransmitters have been immunolocalized on myelinating
oligodendrocytes. Both the AMPA type (47, 134, 257) and
the NMDA type (186, 261) of glutamate receptor are reported to be present on oligodendrocytes. Activation of
NMDA receptors results in an increase in Ca2⫹ in the myelin sheath, while stimulation of AMPA receptors increases
the Ca2⫹ levels in cell somas (261, 262). This indicates that
NMDA receptor densities are higher in the myelin than in
the cell bodies of oligodendrocytes, and that the opposite is
true for AMPA receptors. Supporting this, in oligodendrocyte precursor cells during development, NMDA receptors
are predominantly located in the myelin sheath, while
AMPA receptors are found in the somas (358).
Glutamate released from synaptic vesicles along unmyelinated axons in the white matter activates AMPA type glutamate receptors on OPCs (206, 462), suggesting that the
role of glutamate is to tell OPCs to myelinate active axons.
In line with this, glutamate release is shown (in cultured
mouse dorsal ganglion cells) to promote myelin production
by inducing the formation of cholesterol-rich domains that
mediate membrane interaction between oligodendrocytes
and axons, and by enhancing the local synthesis of myelin
basic protein (MBP), the major protein in the myelin sheath
(428). Recently it was found that glutamate released from
active axons stimulates NMDA receptors on OPCs, which
trigger neuregulin-dependent myelination of axons (241).
These actions of glutamate may be the major mechanism by
which axonal activity induces myelination; they seem to
depend on NMDA receptors (but see De Biase, Ref. 86)
rather than AMPA receptors and are mediated through the
non-receptor Src family tyrosine kinase Fyn (428, 440).
Oligodendroglia also signal back to the neuron to sustain
neuronal viability in response to neuronal activity. A newly
discovered mechanism for this is transfer of exosomes from
oligodendrocytes in response to neuronal release of glutamate activating NMDA and AMPA receptors (125). The
exosome cargo of proteins and RNA gets taken up by neurons in the mouse brain in vivo, improving neuronal survival in conditions of stress. In addition, oligodendrocytes
may improve neuronal function by releasing BDNF in response to activation of metabotropic glutamate receptors
(mGluRs) (18).
However, activation of glutamate receptors on myelin also
underlies the vulnerability of myelin to anoxia-ischemia
(186). Thus the ability to tune myelin function to neural
function is achieved at the expense of a danger of damage,
analogous to synaptic plasticity and learning at the expense
of the danger of excitotoxicity.
Compared with neurons and other brain cells, myelinating
oligodendrocytes and their precursor cells are particularly
710
vulnerable to energy deprivation (17, 308, 349), which can
cause reversal of glutamate transporters, increasing the extracellular glutamate concentration. Energy deprivation
therefore promotes excessive activation of AMPA/kainate
receptors and NMDA receptors that are expressed on oligodendrocyte lineage cells with resulting excitotoxic damage through increased intracellular Ca2⫹ (115, 122, 126,
186, 225, 249, 261, 358, 402). Glutamate receptors of the
AMPA and kainite types are also expressed on myelinated
axons (298, 299), where they similarly can cause damage
due to excessive rise in intracellular Ca2⫹ in response to
glutamate that originates in the axon or enwrapping oligodendrocyte.
While there is evidence for GABAA and GABAB receptors in
OPCs, there are no reports of GABA receptors in myelinating oligodendrocytes (GABAA receptors: Refs. 20, 195,
227, 317, 320, 421, 427; GABAB receptors: Ref. 242).
OPCs receive input from several glutamatergic and/or
GABAergic axons, which disconnect when the OPCs develop into premyelinating oligodendrocytes (124, 208,
448). Such direct neuronal control of OPCs persists even in
the mature brain (124). It may underlie the experienceinduced changes in myelination, indicated by increased
fractional anisotropy observed in the human brain by diffusion tensor magnetic resonance imaging. Such changes
have been reported after cognitive and motor training regimes (107, 367, 404, 456). They are manifested as correlation of interindividual variation in imaging results with
cognitive performance during normal development and
ageing (144).
OPCs are excited by neurons releasing glutamate and
GABA (34, 136, 186, 187, 206, 207, 227, 462). Glutamate
promotes formation of myelin (241, 428), while GABA
stimulates OPC migration (407). GABA, like glutamate,
may exert its effect extrasynaptically, through volume
transmission (421). Glutamate receptor-mediated inhibition of OPC proliferation (131, 455) may lead to enhanced
conduction velocity due to increased internodal lengths
when the axons must be covered by a reduced number of
oligodendrocytes.
There is evidence that NMDA receptors enhance the differentiation of subventricular zone progenitor cells to oligodendrocytes, through activating PKC (60). Neuregulin and
BDNF, presumably from activated axons (302), switch oligodendrocytes from a myelination mode independent of
axonal activity to a mode dependent on NMDA receptors,
activated by glutamate released from active axons (241). A
functional interpretation of this is that once myelination has
proceeded to a certain level, it may be advantageous to
focus the spending of resources on myelinating the axons
that are active. BDNF through its receptor TrkB exerts a
direct effect on oligodendrocytes, promoting myelination,
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and an indirect effect on OPCs, regulating their proliferation (443).
Given the influence of glutamate receptors at multiple functional levels in white matter, they may be involved in a
variety of neuropathological conditions. Glutamate function is therefore an obvious therapeutic target in diseases
involving white matter (57, 256). However, white matter is
home to glia-glia and glia-neuronal interactions mediated
by most of the transmitters operating in grey matter, including glutamatergic, purinergic, GABAergic, glycinergic, adrenergic, cholinergic, dopaminergic, and serotonergic signaling (recent review in Ref. 49).
B. Purines
Neural impulse activity can also influence oligodendroglia
by acting through purinergic receptors: ATP and adenosine
released from active axons can, in a volume transmitter
manner, regulate gene expression, mitosis, differentiation,
and myelination of Schwann cells and oligodendrocytes
(118, 385). Both Schwann cells (the peripheral nervous system’s counterpart of oligodendroglia) and OPCs have P2
receptors, but while several types of P1 receptors are present
in Schwann cells of mice, the OPCs express only A2A and
A2BP1 receptors (119). ATP inhibits early Schwann cell
differentiation and myelination, whereas adenosine stimulates OPC differentiation and myelination. P2Y12 purinergic receptors interact physically with a multifunctional extracellular matrix protein, autotaxin, mediating intermediate states of oligodendrocyte adhesion that are crucial for
the formation of a functional myelin sheath (91). ATP activates P2X7 purinergic receptors leading to an inward current and an increase in cytosolic Ca2⫹; during ischemia,
ATP is released through pannexin hemichannels to cause
damage to oligodendrocytes through these receptors (99).
This effect can be overcome by P2X7 receptor blockers,
which can prevent ischemia induced damage of oligodendrocytes and myelin and improve recovery of action potentials (99).
C. L-Lactate
Once myelin sheaths have formed, the use of lactate by
oligodendrocytes apparently changes. Myelin sheaths in
adult mice were found to release lactate, which was used by
axons (128, 219; commentary in Ref. 347). This is consistent with the notion that long axons are supported by lactate from glycolysis in oligodendrocytes (282). Oligodendrocyte specific knock-down of MCT1 showed that lactate
released from the oligodendroglial compartment is crucial
for axon integrity and function (219). The MCT1 knockdown led to abnormal axon morphology and neuronal
death in organotypic cultures, which could be rescued by
supplying lactate, and caused pathology similar to that seen
in patients with amyotrophic lateral sclerosis (ALS) (219).
ALS patients and SOD1 mutant mice (a mouse model for
ALS) show reduced MCT1 levels in oligodendrocytes. Deficient supply of lactate from oligodendrocytes might therefore contribute to the pathogenesis of ALS and other neurodegenerative diseases.
The elaborate roles of lactate in myelinated axon tracts call
for regulation. It will be interesting to determine to what
extent volume transmission via the lactate receptor HCAR1
is involved. An obvious possibility is that HCAR1-mediated
downregulation of cAMP in response to lactate (213) reduces energy demand and dampens glycolysis and lipolysis,
saving substrates for myelin production. This might underlie some of the beneficial effects of lactate cited in the preceding paragraphs. On the other hand, sustained downregulation of cAMP by HCAR1 activation could be deleterious, since cAMP stimulates vital functions through
protein kinase A (PKA) and exchange proteins directly activated by cAMP (EPACs) (7) and can counteract apoptosis
(174). Along this line, chronic cerebral hypoperfusion in the
absence of energy deficiency, i.e., without significant reduction in the levels of ATP or phosphocreatine, but with transient elevation of lactate, leads to chronic myelin impairment and astrogliosis in corpus callosum (416), possibly
reflecting receptor actions of lactate.
Roles of lactate in oligodendrocytes and myelinated axons
have been reviewed recently (348, 356).
IV. MICROGLIAL TRANSMISSION
The volume transmitter function of lactate (29) pertains
even to white matter. Although a main role of lactate in
oligodendrocyte and axon function is as energy fuel and
precursor for myelin synthesis (348, 356), the effects of
lactate in white matter likely comprise signaling as well as
nutritive support.
Lack of energy caused by limited glucose supply inhibits
myelination due to impaired accessibility of carbon substrates for the synthesis of myelin lipids (260, 349, 359). In
the presence of oxygen, alternative substrates such as lactate, or N-acetylaspartate (288), may overcome shortage of
energy and biosynthetic precursors.
A. Microglia-Neuronal Contacts Affecting
Neuronal Function
Most studies on microglia have been focused on their role in
the pathological brain. In this review we focus on how
microglia interact with neurons in the healthy brain. During
the last years it has become increasingly evident that microglia also play distinct roles in the healthy brain. Like astrocytes, until recently microglia in the healthy brain were
considered resting or quiescent. However, microglia have
been shown to constantly move their processes, surveying
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GUNDERSEN ET AL.
the neuropil (81, 284). During this surveillance, microglia
are highly active, sending their processes to make dynamic
contacts with synapses. These contacts are brief and dependent on neuronal activity (428). Indeed, through their interaction with neuronal elements, microglia can phagocytose
intact synapses, a process that seems to be dependent on
activity in neuronal circuits (411). This suggests that microglia can respond to the functional status of synapses and
modulate experience-dependent synaptic plasticity in the
healthy brain. Further evidence in support of this idea
comes from culture work showing that the presence of microglia increases glutamate signaling in neurons (158, 272),
probably through secretion of neuroactive substances.
Moreover, in intact brain tissue lacking the fractalkine receptor, which is predominantly expressed by microglia
(264, 286), there was reduced hippocampal long-term potentiation (351). However, as fractalkine receptor deficiency triggers activation of microglia (58, 72, 180), this
result does not necessarily reflect physiological regulation
of synaptic activity, but could involve indirect effects caused
by eliciting secretion of neuroactive substances and cytokines from several types of brain cell (6).
In line with the results showing that microglia can affect
synapses, electron microscopic immunocytochemistry has
shown that microglia make contact with synapses (411,
429). On the basis of these findings, the term quadripartite
synapse was coined (25, 351, 364) to also include microglial processes, along with astrocytic processes, and the preand postsynaptic neuronal elements. By immunogold electron microscopy we could show that the delicate microglial
processes contacting synapses contained high levels of actin, enabling them to move in the neuropil (379). Thus the
very fine microglial processes are equipped with a motile
machinery (FIGURE 4). However, the frequency of synapses
receiving direct contacts from surveying microglial processes is rather low at any specific time (379), suggesting
that microglia do not play a major role in physiological
regulation of synaptic signaling. Rather, when microglial
processes survey the neuropil, they probably stop at synapses that are dysfunctional or inactive, leading to synapse
elimination (309, 364, 411).
B. Microglia Express Neurotransmitter
Receptors
The above-described interactions between surveying microglia and neurons are poorly understood. As is the case for
astrocytes, microglia are equipped to respond to neuronal
activity, through expression of a plethora of receptors for
neurotransmitters (137, 191, 334). So far these studies have
mostly been performed in cultured microglia, but some
were done in acutely prepared brain slices, using patchclamp electrophysiology to detect microglial responses, or
using RT-PCR or immunocytochemistry to detect neurotransmitter receptors in microglia. The AMPA type of
712
glutamate receptor has been shown to be present in cultured
microglia (145, 287), along with metabotropic glutamate
receptors: mGluR5 (group I), mGluR2, mGluR3 (group II)
and mGluR4, mGluR6, and mGluR8 (group III) (38, 238,
259, 399, 400, 401). There is evidence for the expression
NMDA receptors on microglia also in the intact brain, although no in situ electrophysiological data have been given
(181). Microglia in culture express metabotropic GABAB
receptors (205), whereas microglial responses to GABAA
receptor activation (284) are thought to be due to indirect
effects (65). Microglial serotonin receptors have also been
detected (5-HT1a, 5-HT1f, 5-HT2a, 5-HT7 serotonin receptors) (203, 371), along with cholinergic receptors, of which
the ␣7 nicotinic type seems to be most prevalent (89, 377),
while the presence of muscarinic receptors in microglia has
been suggested (165). Several studies have detected effects
of stimulating adrenergic receptors on cultured microglia
(127, 337, 422).
Effects of activation of purinergic receptors on microglial
function have been quite extensively studied in response to
brain injury and will not be dealt with in any detail here (for
excellent recent reviews about how purinoceptors regulate
microglial motility and phagocytosis under pathological
conditions, see Ref. 200). Ionotropic P2X and metabotropic P2Y ATP receptors and P1 adenosine receptors have
been detected on microglia (39, 82, 109, 111, 159, 167,
176, 201, 289, 292, 293, 371, 394, 415, 442). A series of
experiments have demonstrated that ATP and its analogs
trigger a rather rapid change of microglia into an activated
phenotype (82, 110, 164, 173). The role of purinergic receptors in regulating physiological responses in surveilling
microglia is poorly understood. Interestingly, a recent study
showed that purinergic receptors regulate motility and
phagocytosis of microglia during postnatal brain development in a Ca2⫹-dependent fashion (392). Moreover, the
ability to respond to purines seems to be a universal property of all microglia, while nonpurinergic transmitters seem
to trigger effects in only subpopulations of microglia (191,
371).
The role of these microglial neurotransmitter receptors is
not clear, let alone for the function of surveying microglia in
the healthy brain. The molecular composition of the contact
points between microglial processes and synapses described
above is unknown. Future studies will reveal whether some
of the neurotransmitter receptors are concentrated in these
sites and whether signal transduction takes place here. It
could be that activation of some of the neurotransmitter
receptors on microglial processes could contribute to the
movement of the processes. For instance, it has been shown
that serotonin responses (via 5-HT2 serotonin receptors) in
microglia resulted in increased movement when an insult
was given to brain tissue (203). Whether such enhanced
motility is an effect of serotonin receptor stimulation also of
surveying microglia, involving increased Ca2⫹ binding to
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NEUROGLIAL TRANSMISSION
microglia
Ter
Sp
nerve terminal
dMp
dendritic spine
500 nm
C
Nor-adrenalin
Nerve
terminal
Glutamate
ACh
GABA
Serotonin
ATP
P2X-R
P2Y-R
Serotonin
β adrenergic receptor
α adrenergic receptor
FIGURE 4. Surveying microglial processes in the healthy brain contact synapses. A: electron microscopic picture
showing that a delicate microglial process
(dMp) labeled for the microglia marker
Iba-1 (gold particles) makes contact with a
presynaptic terminal (ter) and a postsynaptic dendritic spine (sp). The inset shows
higher magnification of vesicular structures in the process. [Modified from Sogn
et al. (379), with permission from John
Wiley and Sons.] B: a delicate microglial
process is equipped with high levels of actin
(gold particles) probably enabling it to move
in brain tissue. Small gold particles (arrows) signal actin and large gold particles
signal Iba-1 (arrowheads). C: schematic
overview of the neurotransmitter receptors found to be present on microglia. ACh,
acetylcholine; nACh-R, nicotinic acetylcholine receptor.
GABAB-R
AMPA-R
mGluR
nACh-R
Microglia
Dendrite
actin in the processes, is not known. In this respect it is
interesting that activation of AMPA receptors could affect
polymerization of actin (68), and thereby contribute to regulation of microglial movement. Again this was found in
AMPA receptor-induced amoeboid microglia. Whether it is
also true for surveying microglia is not known. Another
possibility is that stimulation of the neurotransmitter receptors could help microglia to adapt to different types of ac-
tivation states. Perhaps microglia can sense neuronal activity through activation of their neurotransmitter receptors,
which in turn prevents microglia from being activated. This
idea is supported by, e.g., the effect of cholinergic stimulation of microglia, which seems to inhibit their activation
(377). An exception to the anti-inflammatory role of neurotransmitters is glutamate, which when acting on ionotropic AMPA receptors on microglia can trigger activation
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GUNDERSEN ET AL.
(377) and release of the pro-inflammatory substance tumor
necrosis factor (TNF)-␣ (287). Faced with proinflammatory
stimuli, such as TNF-␣, microglia can release glutamate
(403), and thus probably enter a vicious circle with increased generation of glutamate and TNF-␣. However, microglia seems to have developed also a negative-feedback
loop, because when glutamate acts on group II and III
metabotropic glutamate receptors it attenuates its own release from microglia (259). In line with this is the finding
that activation of group II mGluRs on microglia inhibited
degeneration of dopaminergic neurons after exposure to the
dopaminergic toxin MPP⫹, although this effect was ascribed to increased microglial production of BDNF (423).
Complicating this picture are previous data showing that
stimulation of group II mGluR on microglia induced microglial activation and resulted in a neurotoxic microglial phenotype.
like receptor activation of the NLRP3 inflammasome complex (168). As mentioned above, this effect is mediated by
HCAR1 via arrestin-␤2, independent of cAMP, and causes
reduced activities of Il1B, Nlrp3, Casp1, NF␬B, and IL1␤.
The same or similar mechanisms are known to operate in
microglia and to contribute to inflammatory damage of
brain tissue such as occurs in stroke, hemorrhage, trauma,
and AD (88, 140, 353, 430). Intriguingly, activation of
microglia (425a) as well as of macrophages (354) causes
upregulation of aerobic glycolysis, which results in the production of lactate. Lactate from activated microglia could
turn on HCAR1 at adjacent spine synapses and on the microglia themselves, perhaps mediating autocrine feedback
inhibition after activation, and could be a useful target for
counteracting brain injury of various etiology where inflammation is involved. This hypothesis should soon be
tested.
It is noteworthy that glial cells, through production of
TNF-␣, are directly involved in regulation of synaptic function through “synaptic scaling” (383), which is an overall
homeostatic adjustment of synaptic strength of all synapses
belonging to a neuron. Whereas TNF-␣ upregulates the
strength of excitatory synapses on cortical pyramidal cells
by promoting the insertion of AMPA-type glutamate receptors, it promotes the internalization of AMPA receptors in
the striatum, downregulating the strength of corticostriatal
synapses (221). There has been a debate about the source of
the TNF-␣ in the synaptic scaling process. Both microglia
and astrocytes are candidates for such TNF-␣ secretion
(383). In brain inflammation, as a consequence of injury or
disease, the secretion of massive amounts of TNF-␣ by activated microglia may transform the physiological actions
of the cytokine into harmful ones (362). Recent findings
suggest that TNF-␣ derived from astrocytes rather than
from microglia is required for the maintenance of a compensatory increase in excitatory synaptic strength after denervation (24).
V. CONCLUSIONS
Concerning the microglial purinoceptors, their role is found
to be important for development and maintenance of a wide
variety of brain inflammation processes. The latter is not the
topic of the present review and will not be described further
here. A comprehensive overview of the function of purinoceptors (as well as of other neurotransmitter receptors) in
microglia was given by Kettenmann et al. (191). However,
it should be mentioned that, in particular, the P2X7 receptor seems to be located on the whole population of microglia throughout the brain (454), suggesting that this receptor participates in universal microglial processes.
Whether microglia react to lactate via HCAR1 has not been
determined, but this seems a likely possibility, considering
their kinship with inflammatory cells. Thus macrophages
and monocytes in vitro and in vivo react to lactate, which
counteracts inflammatory tissue injury by inhibiting Toll-
714
Why neuroglial transmission? Neurotransmission at synapses is high resolution in time and space, on the order of
milliseconds and tenths of microns, elicited by an axon
action potential. Transmission involving neuroglia can
modulate synaptic neurotransmission, based on local conditions in the neural tissue, in many cases integrating over
longer times and through tissue volumes that contain many
synapses. This provides a mode of regulation complementary to the transmission directly evoked by nerve impulses
invading nerve endings. However, astrocytes can respond
to synaptic activity by highly local Ca2⫹ transients, leading
to release of gliotransmitters that signal back to synapses
within a timescale of seconds. Although no clear synaptic
specializations in the contacts between astrocytic processes
and synaptic elements have been detected, the distance that
the gliotransmitters must diffuse before reaching receptors
to act on is probably short and in the micron scale. Such
local changes in the intracellular concentration of Ca2⫹ can
probably sum up to give larger transients, spread through
the complex astrocytic ramifications to other parts of the
cell, and further through gap junctions to other regions of
the astrocytic network, the concentration transient declining with the distance. The astrocytic network even communicates with oligodendrocytes via gap junctions. At any
point in the network, the triggering of gliotransmitter release will depend on the resultant sum of changes originating in different parts of the surroundings. As a result of this
intercellular spread of Ca2⫹, a gliotransmitter may be released by Ca2⫹-dependent exocytosis in a similar way as
neurotransmitters at synapses (e.g., glutamate, ATP, D-serine), or through plasma membrane transporters or channels
(e.g., lactate through MCTs, or glutamate and GABA
through bestrophin 1). Once released, the transmitter may
diffuse through the extracellular space to reach receptor
sites at short or long distance, as referred to by the term
volume transmission.
Physiol Rev • VOL 95 • JULY 2015 • www.prv.org
NEUROGLIAL TRANSMISSION
A major controversy has been whether gliotransmitters are
released through exocytosis of synaptic like microvesicles in
glia. Conflicting findings may be ascribed to the use of different experimental conditions. It now appears that both
exocytotic and nonvesicular release of gliotransmitters occurs. The challenge for the future is to delineate under
which circumstances the different modes of release predominate.
The idea has recently emerged that lactate, a product of
brain metabolism, functions as a gliotransmitter. It may act
through one or more lactate receptor proteins, as well as
through affecting local pH and redox state in central nervous system tissue. The receptor actions of lactate may help
resolve controversies over which cells are more important
for lactate production, and how lactate counteracts brain
tissue damage in cerebral stroke and mechanical trauma.
Beneficial effects of physical exercise on brain health may
partly depend on lactate from active muscles entering the
brain to act on elements of the gliotransmitter mechanisms
of lactate, which may be further enhanced by lactate released from astrocytes activated by neurons during exercise.
Surveying microglia in the healthy brain have recently been
discovered to enter into contact with neuronal synapses and
to have receptors for neurotransmitters/gliotransmitters.
Through these, microglia may detect to what extent synapses are active and potentially contribute to elimination of
nonactive ones. Future studies will reveal the functional
consequences of activation of neurotransmitter receptors in
surveying microglia, and whether there are subpopulations
of microglia with different expression of neurotransmitter
receptors. A major future undertaking will be to determine
whether different brain regions are populated by different
subtypes of microglia.
Major questions outstanding are the exact roles of neuroglial transmission for normal brain function, and how and
to what extent pathological changes in neuroglial transmission contribute to disease processes. The increased understanding to be gained from answering these questions can
be expected to impact importantly on managing brain disease.
NOTE ADDED IN PROOF
An important new facet of the gliotransmitter role of lactate
is revealed in the just published report by Sotelo-Hitschfeld
et al. (381a). With the use of novel genetically encoded
fluorescence nanosensors, these authors show that astrocytes at rest maintain a cytosolic lactate pool in excess of the
thermodynamic equilibrium through MCTs, due to the
presence of a lactate-permeable anion channel. In response
to increased extracellular K⫹ and depolarization of the glial
plasma membrane during neural activity, this channel
opens to release lactate in a manner enhanced by lactate
itself, providing a means for rapid and focused stimulation
of lactate receptors such as HCAR1.
ACKNOWLEDGMENTS
V. Gundersen and L. H. Bergersen contributed equally to
this work.
Address for correspondence: V. Gundersen, SN-Lab, Div.
of Anatomy, Institute of Basic Medical Sciences, Univ. of
Oslo, PB1105 Blindern, 0317 Oslo, Norway (e-mail: vidar.
gundersen@medisin.uio.no); or L. H. Bergersen, Dept. of
Oral Biology, Univ. of Oslo, PB1052 Blindern, 0316 Oslo,
Norway (e-mail: l.h.bergersen@medisin.uio.no).
GRANTS
This work has been supported by grants from the University
of Oslo, Anders Jahre’s Foundation for the Advancement of
Science, “Nasjonalforeningen for Folkehelsen,” and The
Norwegian Research Council (including Unikard, a joint
Research Council-Health Authority grant), Norway, as
well as from the University of Copenhagen and the Lundbeck Foundation, Denmark.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared
by the authors.
REFERENCES
1. Abdullaev IF, Rudkouskaya A, Schools GP, Kimelberg HK, Mongin AA. Pharmacological comparison of swelling-activated excitatory amino acid release and Cl⫺ currents
in cultured rat astrocytes. J Physiol 572: 677– 689, 2006.
2. Abudara V, Bechberger J, Freitas-Andrade M, De BM, Wang N, Bultynck G, Naus CC,
Leybaert L, Giaume C. The connexin43 mimetic peptide Gap19 inhibits hemichannels
without altering gap junctional communication in astrocytes. Front Cell Neurosci 8:
306, 2014.
3. Agnati LF, Fuxe K, Zoli M, Ozini I, Toffano G, Ferraguti F. A correlation analysis of the
regional distribution of central enkephalin and beta-endorphin immunoreactive terminals and of opiate receptors in adult and old male rats. Evidence for the existence of
two main types of communication in the central nervous system: the volume transmission and the wiring transmission. Acta Physiol Scand 128: 201–207, 1986.
4. Agnati LF, Guidolin D, Guescini M, Genedani S, Fuxe K. Understanding wiring and
volume transmission. Brain Res Rev 64: 137–159, 2010.
5. Ahmed K, Tunaru S, Tang C, Muller M, Gille A, Sassmann A, Hanson J, Offermanns S.
An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through
GPR81. Cell Metab 11: 311–319, 2010.
6. Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci 2:
734 –744, 2001.
7. Almahariq M, Mei FC, Cheng X. Cyclic AMP sensor EPAC proteins and energy
homeostasis. Trends Endocrinol Metab 25: 60 –71, 2014.
8. Andersson M, Blomstrand F, Hanse E. Astrocytes play a critical role in transient
heterosynaptic depression in the rat hippocampal CA1 region. J Physiol 585: 843– 852,
2007.
9. Angulo MC, Kozlov AS, Charpak S, Audinat E. Glutamate released from glial cells
synchronizes neuronal activity in the hippocampus. J Neurosci 24: 6920 – 6927, 2004.
Physiol Rev • VOL 95 • JULY 2015 • www.prv.org
715
GUNDERSEN ET AL.
10. Anlauf E, Derouiche A. Astrocytic exocytosis vesicles and glutamate: a high-resolution
immunofluorescence study. Glia 49: 96 –106, 2005.
11. Araque A, Carmignoto G, Haydon PG, Oliet SH, Robitaille R, Volterra A. Gliotransmitters travel in time and space. Neuron 81: 728 –739, 2014.
12. Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22: 208 –215, 1999.
32. Bergersen LH, Magistretti PJ, Pellerin L. Selective postsynaptic co-localization of
MCT2 with AMPA receptor GluR2/3 subunits at excitatory synapses exhibiting AMPA
receptor trafficking. Cereb Cortex 15: 361–370, 2005.
33. Bergersen LH, Morland C, Ormel L, Rinholm JE, Larsson M, Wold JF, Roe AT, Stranna
A, Santello M, Bouvier D, Ottersen OP, Volterra A, Gundersen V. Immunogold
detection of L-glutamate and D-serine in small synaptic-like microvesicles in adult
hippocampal astrocytes. Cereb Cortex 22: 1690 –1697, 2012.
13. Arcuino G, Lin JH, Takano T, Liu C, Jiang L, Gao Q, Kang J, Nedergaard M. Intercellular calcium signaling mediated by point-source burst release of ATP. Proc Natl Acad
Sci USA 99: 9840 –9845, 2002.
34. Bergles DE, Roberts JD, Somogyi P, Jahr CE. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 405: 187–191, 2000.
14. Arnsten AF, Wang MJ, Paspalas CD. Neuromodulation of thought: flexibilities and
vulnerabilities in prefrontal cortical network synapses. Neuron 76: 223–239, 2012.
35. Bezzi P, Carmignoto G, Pasti L, Vesce S, Rossi D, Rizzini BL, Pozzan T, Volterra A.
Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature
391: 281–285, 1998.
15. Attwell D, Gibb A. Neuroenergetics and the kinetic design of excitatory synapses. Nat
Rev Neurosci 6: 841– 849, 2005.
16. Azevedo FA, Carvalho LR, Grinberg LT, Farfel JM, Ferretti RE, Leite RE, Jacob FW,
Lent R, Herculano-Houzel S. Equal numbers of neuronal and nonneuronal cells make
the human brain an isometrically scaled-up primate brain. J Comp Neurol 513: 532–
541, 2009.
17. Back SA, Luo NL, Mallinson RA, O’Malley JP, Wallen LD, Frei B, Morrow JD, Petito
CK, Roberts CT Jr, Murdoch GH, Montine TJ. Selective vulnerability of preterm white
matter to oxidative damage defined by F2-isoprostanes. Ann Neurol 58: 108 –120,
2005.
18. Bagayogo IP, Dreyfus CF. Regulated release of BDNF by cortical oligodendrocytes is
mediated through metabotropic glutamate receptors and the PLC pathway. ASN
Neuro 1: 2009.
19. Bal-Price A, Moneer Z, Brown GC. Nitric oxide induces rapid, calcium-dependent
release of vesicular glutamate and ATP from cultured rat astrocytes. Glia 40: 312–323,
2002.
20. Balia M, Velez-Fort M, Passlick S, Schafer C, Audinat E, Steinhauser C, Seifert G,
Angulo MC. Postnatal down-regulation of the GABAA receptor gamma2 subunit in
neocortical NG2 cells accompanies synaptic-to-extrasynaptic switch in the GABAergic
transmission mode. Cereb Cortex. In press.
21. Ballerini P, Rathbone MP, Di IP, Renzetti A, Giuliani P, D’Alimonte I, Trubiani O,
Caciagli F, Ciccarelli R. Rat astroglial P2Z (P2X7) receptors regulate intracellular
calcium and purine release. Neuroreport 7: 2533–2537, 1996.
22. Barnabe-Heider F, Miller FD. Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways. J Neurosci 23: 5149 –5160, 2003.
23. Basarsky TA, Feighan D, MacVicar BA. Glutamate release through volume-activated
channels during spreading depression. J Neurosci 19: 6439 – 6445, 1999.
24. Becker D, Zahn N, Deller T, Vlachos A. Tumor necrosis factor alpha maintains
denervation-induced homeostatic synaptic plasticity of mouse dentate granule cells.
Front Cell Neurosci 7: 257, 2013.
25. Bennett MR. Synaptic P2X7 receptor regenerative-loop hypothesis for depression.
Aust N Z J Psychiatry 41: 563–571, 2007.
36. Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De CE, Vescovi A, Bagetta G,
Kollias G, Meldolesi J, Volterra A. CXCR4-activated astrocyte glutamate release via
TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 4: 702–710,
2001.
37. Bezzi P, Gundersen V, Galbete JL, Seifert G, Steinhauser C, Pilati E, Volterra A.
Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci 7: 613– 620, 2004.
38. Biber K, Laurie DJ, Berthele A, Sommer B, Tolle TR, Gebicke-Harter PJ, van CD,
Boddeke HW. Expression and signaling of group I metabotropic glutamate receptors
in astrocytes and microglia. J Neurochem 72: 1671–1680, 1999.
39. Boucsein C, Zacharias R, Farber K, Pavlovic S, Hanisch UK, Kettenmann H. Purinergic
receptors on microglial cells: functional expression in acute brain slices and modulation of microglial activation in vitro. Eur J Neurosci 17: 2267–2276, 2003.
40. Bouzat P, Magistretti PJ, Oddo M. Hypertonic lactate and the injured brain: facts and
the potential for positive clinical implications. Intensive Care Med 40: 920 –921, 2014.
41. Bowens NH, Dohare P, Kuo YH, Mongin AA. DCPIB, the proposed selective blocker
of volume-regulated anion channels, inhibits several glutamate transport pathways in
glial cells. Mol Pharmacol 83: 22–32, 2013.
42. Bowser DN, Khakh BS. ATP excites interneurons and astrocytes to increase synaptic
inhibition in neuronal networks. J Neurosci 24: 8606 – 8620, 2004.
43. Bowser DN, Khakh BS. Two forms of single-vesicle astrocyte exocytosis imaged with
total internal reflection fluorescence microscopy. Proc Natl Acad Sci USA 104: 4212–
4217, 2007.
45. Bozzo L, Puyal J, Chatton JY. Lactate modulates the activity of primary cortical neurons through a receptor-mediated pathway. PLoS One 8: e71721, 2013.
46. Bramham CR, Torp R, Zhang N, Storm-Mathisen J, Ottersen OP. Distribution of
glutamate-like immunoreactivity in excitatory hippocampal pathways: a semiquantitative electron microscopic study in rats. Neuroscience 39: 405– 417, 1990.
47. Brand-Schieber E, Werner P. (⫹/⫺)-Alpha-amino-3-hydroxy-5-methylisoxazole-4propionic acid and kainate receptor subunit expression in mouse versus rat spinal
cord white matter: similarities in astrocytes but differences in oligodendrocytes. Neurosci Lett 345: 126 –130, 2003.
26. Berger UV, DeSilva TM, Chen W, Rosenberg PA. Cellular and subcellular mRNA
localization of glutamate transporter isoforms GLT1a and GLT1b in rat brain by in situ
hybridization. J Comp Neurol 492: 78 – 89, 2005.
48. Bushong EA, Martone ME, Jones YZ, Ellisman MH. Protoplasmic astrocytes in CA1
stratum radiatum occupy separate anatomical domains. J Neurosci 22: 183–192, 2002.
27. Bergersen LH. Is lactate food for neurons? Comparison of monocarboxylate transporter subtypes in brain and muscle. Neuroscience 145: 11–19, 2007.
49. Butt AM, Fern RF, Matute C. Neurotransmitter signaling in white matter. Glia 62:
1762–1779, 2014.
28. Bergersen LH. Lactate transport and signaling in the brain: potential therapeutic
targets and roles in body-brain interaction. J Cereb Blood Flow Metab 35: 176 –185,
2015.
50. Caesar K, Hashemi P, Douhou A, Bonvento G, Boutelle MG, Walls AB, Lauritzen M.
Glutamate receptor-dependent increments in lactate, glucose and oxygen metabolism evoked in rat cerebellum in vivo. J Physiol 586: 1337–1349, 2008.
29. Bergersen LH, Gjedde A. Is lactate a volume transmitter of metabolic states of the
brain? Front Neuroenerget 4: 5, 2012.
30. Bergersen LH, Gundersen V. Morphological evidence for vesicular glutamate release
from astrocytes. Neuroscience 158: 260 –265, 2009.
51. Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y,
Lubischer JL, Krieg PA, Krupenko SA, Thompson WJ, Barres BA. A transcriptome
database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28: 264 –278, 2008.
31. Bergersen LH, Lauritzen KH, Lauritzen F, Puchades M, Gjedde A. Lactate receptor
locations link neurotransmission, neurovascular coupling, and brain energy metabolism. J Cereb Blood Flow Metab 32: S183, 2012.
53. Cai TQ, Ren N, Jin L, Cheng K, Kash S, Chen R, Wright SD, Taggart AK, Waters MG.
Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biochem Biophys Res
Commun 377: 987–991, 2008.
716
Physiol Rev • VOL 95 • JULY 2015 • www.prv.org
NEUROGLIAL TRANSMISSION
54. Calegari F, Coco S, Taverna E, Bassetti M, Verderio C, Corradi N, Matteoli M, Rosa P.
A regulated secretory pathway in cultured hippocampal astrocytes. J Biol Chem 274:
22539 –22547, 1999.
74. Crippa D, Schenk U, Francolini M, Rosa P, Verderio C, Zonta M, Pozzan T, Matteoli
M, Carmignoto G. Synaptobrevin2-expressing vesicles in rat astrocytes: insights into
molecular characterization, dynamics and exocytosis. J Physiol 570: 567–582, 2006.
55. Cali C, Lopatar J, Petrelli F, Pucci L, Bezzi P. G-protein coupled receptor-evoked
glutamate exocytosis from astrocytes: role of prostaglandins. Neural Plast 2014:
254574, 2014.
75. Cruz NF, Adachi K, Dienel GA. Rapid efflux of lactate from cerebral cortex during
K⫹-induced spreading cortical depression. J Cereb Blood Flow Metab 19: 380 –392,
1999.
56. Cali C, Marchaland J, Regazzi R, Bezzi P. SDF 1-alpha (CXCL12) triggers glutamate
exocytosis from astrocytes on a millisecond time scale: imaging analysis at the singlevesicle level with TIRF microscopy. J Neuroimmunol 198: 82–91, 2008.
76. Cureton EL, Kwan RO, Dozier KC, Sadjadi J, Pal JD, Victorino GP. A different view of
lactate in trauma patients: protecting the injured brain. J Surg Res 159: 468 – 473, 2010.
57. Cao N, Yao ZX. Oligodendrocyte N-methyl-D-aspartate receptor signaling: insights
into its functions. Mol Neurobiol 47: 845– 856, 2013.
58. Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D,
Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR,
Ransohoff RM. Control of microglial neurotoxicity by the fractalkine receptor. Nat
Neurosci 9: 917–924, 2006.
59. Carlyle BC, Nairn AC, Wang M, Yang Y, Jin LE, Simen AA, Ramos BP, Bordner KA,
Craft GE, Davies P, Pletikos M, Sestan N, Arnsten AF, Paspalas CD. cAMP-PKA
phosphorylation of tau confers risk for degeneration in aging association cortex. Proc
Natl Acad Sci USA 111: 5036 –5041, 2014.
60. Cavaliere F, Benito-Munoz M, Panicker M, Matute C. NMDA modulates oligodendrocyte differentiation of subventricular zone cells through PKC activation. Front Cell
Neurosci 7: 261, 2013.
61. Cerdán S, Rodrigues TB, Sierra A, Benito M, Fonseca LL, Fonseca CP, Garcia-Martin
ML. The redox switch/redox coupling hypothesis. Neurochem Int 48: 523–530, 2006.
77. D’Ascenzo M, Fellin T, Terunuma M, Revilla-Sanchez R, Meaney DF, Auberson YP,
Moss SJ, Haydon PG. mGluR5 stimulates gliotransmission in the nucleus accumbens.
Proc Natl Acad Sci USA 104: 1995–2000, 2007.
78. Danesh-Meyer HV, Kerr NM, Zhang J, Eady EK, O’Carroll SJ, Nicholson LF, Johnson
CS, Green CR. Connexin43 mimetic peptide reduces vascular leak and retinal ganglion cell death following retinal ischaemia. Brain 135: 506 –520, 2012.
79. Dani JW, Chernjavsky A, Smith SJ. Neuronal activity triggers calcium waves in hippocampal astrocyte networks. Neuron 8: 429 – 440, 1992.
80. Danik M, Cassoly E, Manseau F, Sotty F, Mouginot D, Williams S. Frequent coexpression of the vesicular glutamate transporter 1 and 2 genes, as well as coexpression with
genes for choline acetyltransferase or glutamic acid decarboxylase in neurons of rat
brain. J Neurosci Res 81: 506 –521, 2005.
81. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan
WB. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci
8: 752–758, 2005.
62. Chaudhary N, Pfluger PT. Metabolic benefits from Sirt1 and Sirt1 activators. Curr Opin
Clin Nutr Metab Care 12: 431– 437, 2009.
82. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan
WB. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci
8: 752–758, 2005.
63. Chen MJ, Kress B, Han X, Moll K, Peng W, Ji RR, Nedergaard M. Astrocytic CX43
hemichannels and gap junctions play a crucial role in development of chronic neuropathic pain following spinal cord injury. Glia 60: 1660 –1670, 2012.
83. Davidson JO, Drury PP, Green CR, Nicholson LF, Bennet L, Gunn AJ. Connexin
hemichannel blockade is neuroprotective after asphyxia in preterm fetal sheep. PLoS
One 9: e96558, 2014.
64. Chen X, Wang L, Zhou Y, Zheng LH, Zhou Z. “Kiss-and-run” glutamate secretion in
cultured and freshly isolated rat hippocampal astrocytes. J Neurosci 25: 9236 –9243,
2005.
84. Davidson JO, Green CR, Bennet L, Gunn AJ. Battle of the hemichannels– connexins
and pannexins in ischemic brain injury. Int J Dev Neurosci doi:
10.1016/j.ijdevneu.2014.12.007.
65. Cheung G, Kann O, Kohsaka S, Faerber K, Kettenmann H. GABAergic activities
enhance macrophage inflammatory protein-1alpha release from microglia (brain macrophages) in postnatal mouse brain. J Physiol 587: 753–768, 2009.
85. Davidson JO, Green CR, Nicholson LF, O’Carroll SJ, Fraser M, Bennet L, Gunn AJ.
Connexin hemichannel blockade improves outcomes in a model of fetal ischemia. Ann
Neurol 71: 121–132, 2012.
66. Cho J, Shin MK, Kim D, Lee I, Kim S, Kang H. Treadmill running reverses cognitive
declines due to Alzheimer’s disease. Med Sci Sports Exercise. In press.
86. De Biase LM, Kang SH, Baxi EG, Fukaya M, Pucak ML, Mishina M, Calabresi PA,
Bergles DE. NMDA receptor signaling in oligodendrocyte progenitors is not required
for oligodendrogenesis and myelination. J Neurosci 31: 12650 –12662, 2011.
67. Choi HB, Gordon GR, Zhou N, Tai C, Rungta RL, Martinez J, Milner TA, Ryu JK,
McLarnon JG, Tresguerres M, Levin LR, Buck J, MacVicar BA. Metabolic communication between astrocytes and neurons via bicarbonate-responsive soluble adenylyl
cyclase. Neuron 75: 1094 –1104, 2012.
87. De Bruin LA, Schasfoort EM, Steffens AB, Korf J. Effects of stress and exercise on rat
hippocampus and striatum extracellular lactate. Am J Physiol Regul Integr Comp Physiol
259: R773–R779, 1990.
68. Christensen RN, Ha BK, Sun F, Bresnahan JC, Beattie MS. Kainate induces rapid
redistribution of the actin cytoskeleton in ameboid microglia. J Neurosci Res 84: 170 –
181, 2006.
88. De Rivero Vaccari JP, Dietrich WD, Keane RW. Activation and regulation of cellular
inflammasomes: gaps in our knowledge for central nervous system injury. J Cereb
Blood Flow Metab 34: 369 –375, 2014.
69. Coco M, Caggia S, Musumeci G, Perciavalle V, Graziano AC, Pannuzzo G, Cardile V.
Sodium L-lactate differently affects brain-derived neurothrophic factor, inducible nitric oxide synthase, and heat shock protein 70 kDa production in human astrocytes
and SH-SY5Y cultures. J Neurosci Res 91: 313–320, 2013.
89. De Simone R, Ajmone-Cat MA, Carnevale D, Minghetti L. Activation of alpha7 nicotinic acetylcholine receptor by nicotine selectively up-regulates cyclooxygenase-2 and
prostaglandin E2 in rat microglial cultures. J Neuroinflammation 2: 4, 2005.
70. Coco S, Calegari F, Pravettoni E, Pozzi D, Taverna E, Rosa P, Matteoli M, Verderio C.
Storage and release of ATP from astrocytes in culture. J Biol Chem 278: 1354 –1362,
2003.
90. Deng Q, Terunuma M, Fellin T, Moss SJ, Haydon PG. Astrocytic activation of A1
receptors regulates the surface expression of NMDA receptors through a Src kinase
dependent pathway. Glia 59: 1084 –1093, 2011.
71. Contreras JE, Saez JC, Bukauskas FF, Bennett MV. Gating and regulation of connexin
43 (Cx43) hemichannels. Proc Natl Acad Sci USA 100: 11388 –11393, 2003.
91. Dennis J, Morgan MK, Graf MR, Fuss B. P2Y12 receptor expression is a critical
determinant of functional responsiveness to ATX’s MORFO domain. Purinergic Signal
8: 181–190, 2012.
72. Corona AW, Huang Y, O’Connor JC, Dantzer R, Kelley KW, Popovich PG, Godbout
JP. Fractalkine receptor (CX3CR1) deficiency sensitizes mice to the behavioral
changes induced by lipopolysaccharide. J Neuroinflammation 7: 93, 2010.
92. Dhar-Chowdhury P, Malester B, Rajacic P, Coetzee WA. The regulation of ion channels and transporters by glycolytically derived ATP. Cell Mol Life Sci 64: 3069 –3083,
2007.
73. Cotrina ML, Lin JH, Alves-Rodrigues A, Liu S, Li J, Azmi-Ghadimi H, Kang J, Naus CC,
Nedergaard M. Connexins regulate calcium signaling by controlling ATP release. Proc
Natl Acad Sci USA 95: 15735–15740, 1998.
93. Di Castro MA, Chuquet J, Liaudet N, Bhaukaurally K, Santello M, Bouvier D, Tiret P,
Volterra A. Local Ca2⫹ detection and modulation of synaptic release by astrocytes.
Nat Neurosci 14: 1276 –1284, 2011.
Physiol Rev • VOL 95 • JULY 2015 • www.prv.org
717
GUNDERSEN ET AL.
94. Dienel GA. Brain lactate metabolism: the discoveries and the controversies. J Cereb
Blood Flow Metab 32: 1107–1138, 2012.
117. Fiacco TA, McCarthy KD. Intracellular astrocyte calcium waves in situ increase the
frequency of spontaneous AMPA receptor currents in CA1 pyramidal neurons. J
Neurosci 24: 722–732, 2004.
95. Dienel GA. Fueling and imaging brain activation. ASN Neuro 4: 2012.
96. Dienel GA. Astrocytic energetics during excitatory neurotransmission: what are contributions of glutamate oxidation and glycolysis? Neurochem Int 63: 244 –258, 2013.
97. Dienel GA. Lactate shuttling and lactate use as fuel after traumatic brain injury: metabolic considerations. J Cereb Blood Flow Metab 34: 1736 –1748, 2014.
98. Domercq M, Brambilla L, Pilati E, Marchaland J, Volterra A, Bezzi P. P2Y1 receptorevoked glutamate exocytosis from astrocytes: control by tumor necrosis factor-alpha
and prostaglandins. J Biol Chem 281: 30684 –30696, 2006.
99. Domercq M, Perez-Samartin A, Aparicio D, Alberdi E, Pampliega O, Matute C. P2X7
receptors mediate ischemic damage to oligodendrocytes. Glia 58: 730 –740, 2010.
100. Domercq M, Vazquez-Villoldo NF, Matute C. Neurotransmitter signaling in the
pathophysiology of microglia. Front Cell Neurosci 7: 49, 2013.
101. Doyle JP, Dougherty JD, Heiman M, Schmidt EF, Stevens TR, Ma G, Bupp S, Shrestha
P, Shah RD, Doughty ML, Gong S, Greengard P, Heintz N. Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell 135:
749 –762, 2008.
102. Duan S, Anderson CM, Keung EC, Chen Y, Chen Y, Swanson RA. P2X7 receptormediated release of excitatory amino acids from astrocytes. J Neurosci 23: 1320 –
1328, 2003.
104. Dvorak CA, Liu C, Shelton J, Kuei C, Sutton SW, Lovenberg TW, Carruthers NI.
Identification of hydroxybenzoic acids as selective lactate receptor (GPR81) agonists
with antilipolytic effects. ACS Med Chem Lett 3: 637– 639, 2012.
105. El-Hassar L, Simen AA, Duque A, Patel KD, Kaczmarek LK, Arnsten AF, Yeckel MF.
Disrupted in schizophrenia 1 modulates medial prefrontal cortex pyramidal neuron
activity through cAMP regulation of transient receptor potential C and small-conductance K channels. Biol Psychiatry 76: 476 – 485, 2014.
106. Emsley JG, Macklis JD. Astroglial heterogeneity closely reflects the neuronal-defined
anatomy of the adult murine CNS. Neuron Glia Biol 2: 175–186, 2006.
107. Engvig A, Fjell AM, Westlye LT, Moberget T, Sundseth O, Larsen VA, Walhovd KB.
Memory training impacts short-term changes in aging white matter: a longitudinal
diffusion tensor imaging study. Hum Brain Mapp 33: 2390 –2406, 2012.
108. Enkvist MO, McCarthy KD. Astroglial gap junction communication is increased by
treatment with either glutamate or high K⫹ concentration. J Neurochem 62: 489 – 495,
1994.
109. Fang KM, Yang CS, Sun SH, Tzeng SF. Microglial phagocytosis attenuated by shortterm exposure to exogenous ATP through P2X receptor action. J Neurochem 111:
1225–1237, 2009.
110. Farber K, Kettenmann H. Purinergic signaling and microglia. Pflügers Arch 452: 615–
621, 2006.
111. Farber K, Markworth S, Pannasch U, Nolte C, Prinz V, Kronenberg G, Gertz K,
Endres M, Bechmann I, Enjyoji K, Robson SC, Kettenmann H. The ectonucleotidase
cd39/ENTPDase1 modulates purinergic-mediated microglial migration. Glia 56: 331–
341, 2008.
112. Farmer J, Zhao X, van PH, Wodtke K, Gage FH, Christie BR. Effects of voluntary
exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male
Sprague-Dawley rats in vivo. Neuroscience 124: 71–79, 2004.
113. Fellin T, Halassa MM, Terunuma M, Succol F, Takano H, Frank M, Moss SJ, Haydon
PG. Endogenous nonneuronal modulators of synaptic transmission control cortical
slow oscillations in vivo. Proc Natl Acad Sci USA 106: 15037–15042, 2009.
114. Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA
receptors. Neuron 43: 729 –743, 2004.
118. Fields RD. Volume transmission in activity-dependent regulation of myelinating glia.
Neurochem Int 45: 503–509, 2004.
119. Fields RD. Nerve impulses regulate myelination through purinergic signalling. Novartis
Found Symp 276: 148 –158, 2006.
120. Fields RD. White matter in learning, cognition and psychiatric disorders. Trends Neurosci 31: 361–370, 2008.
121. Fioretti B, Castigli E, Calzuola I, Harper AA, Franciolini F, Catacuzzeno L. NPPB block
of the intermediate-conductance Ca2⫹-activated K⫹ channel. Eur J Pharmacol 497:
1– 6, 2004.
122. Follett PL, Rosenberg PA, Volpe JJ, Jensen FE. NBQX attenuates excitotoxic injury in
developing white matter. J Neurosci 20: 9235–9241, 2000.
123. Fremeau RT Jr, Burman J, Qureshi T, Tran CH, Proctor J, Johnson J, Zhang H, Sulzer
D, Copenhagen DR, Storm-Mathisen J, Reimer RJ, Chaudhry FA, Edwards RH. The
identification of vesicular glutamate transporter 3 suggests novel modes of signaling by
glutamate. Proc Natl Acad Sci USA 99: 14488 –14493, 2002.
124. Fröhlich N, Nagy BF, Hovhannisyan AF, Kukley M. Fate of neuron-glia synapses during
proliferation and differentiation of NG2 cells. J Anat 219: 18 –32, 2011.
125. Fruhbeis C, Frohlich D, Kuo WP, Amphornrat J, Thilemann S, Saab AS, Kirchhoff F,
Mobius W, Goebbels S, Nave KA, Schneider A, Simons M, Klugmann M, Trotter J,
Kramer-Albers EM. Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol 11: e1001604, 2013.
126. Fu Y, Sun W, Shi Y, Shi R, Cheng JX. Glutamate excitotoxicity inflicts paranodal myelin
splitting and retraction. PLoS One 4: e6705, 2009.
127. Fujita H, Tanaka J, Maeda N, Sakanaka M. Adrenergic agonists suppress the proliferation of microglia through beta 2-adrenergic receptor. Neurosci Lett 242: 37– 40,
1998.
128. Funfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J, Brinkmann BG,
Kassmann CM, Tzvetanova ID, Mobius W, Diaz F, Meijer D, Suter U, Hamprecht B,
Sereda MW, Moraes CT, Frahm J, Goebbels S, Nave KA. Glycolytic oligodendrocytes
maintain myelin and long-term axonal integrity. Nature 485: 517–521, 2012.
129. Furness DN, Dehnes Y, Akhtar AQ, Rossi DJ, Hamann M, Grutle NJ, Gundersen V,
Holmseth S, Lehre KP, Ullensvang K, Wojewodzic M, Zhou Y, Attwell D, Danbolt
NC. A quantitative assessment of glutamate uptake into hippocampal synaptic terminals and astrocytes: new insights into a neuronal role for excitatory amino acid transporter 2 (EAAT2). Neuroscience 157: 80 –94, 2008.
130. Fuxe K, Dahlstrom AB, Jonsson G, Marcellino D, Guescini M, Dam M, Manger P,
Agnati L. The discovery of central monoamine neurons gave volume transmission to
the wired brain. Prog Neurobiol 90: 82–100, 2010.
131. Gallo V, Zhou JM, McBain CJ, Wright P, Knutson PL, Armstrong RC. Oligodendrocyte
progenitor cell proliferation and lineage progression are regulated by glutamate receptor-mediated K⫹ channel block. J Neurosci 16: 2659 –2670, 1996.
132. Gamo NJ, Duque A, Paspalas CD, Kata A, Fine R, Boven L, Bryan C, Lo T, Anighoro
K, Bermudez L, Peng K, Annor A, Raja A, Mansson E, Taylor SR, Patel K, Simen AA,
Arnsten AF. Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal
cognitive dysfunction. Transl Psychiatry 3: e328, 2013.
133. Gandhi GK, Cruz NF, Ball KK, Dienel GA. Astrocytes are poised for lactate trafficking
and release from activated brain and for supply of glucose to neurons. J Neurochem
111: 522–536, 2009.
134. Garcia-Barcina JM, Matute C. Expression of kainate-selective glutamate receptor
subunits in glial cells of the adult bovine white matter. Eur J Neurosci 8: 2379 –2387,
1996.
115. Fern R, Möller T. Rapid ischemic cell death in immature oligodendrocytes: a fatal
glutamate release feedback loop. J Neurosci 20: 34 – 42, 2000.
135. Garré JM, Retamal MA, Cassina P, Barbeito L, Bukauskas FF, Saez JC, Bennett MV,
Abudara V. FGF-1 induces ATP release from spinal astrocytes in culture and opens
pannexin and connexin hemichannels. Proc Natl Acad Sci USA 107: 22659 –22664,
2010.
116. Feustel PJ, Jin Y, Kimelberg HK. Volume-regulated anion channels are the predominant contributors to release of excitatory amino acids in the ischemic cortical penumbra. Stroke 35: 1164 –1168, 2004.
136. Ge WP, Zhou W, Luo Q, Jan LY, Jan YN. Dividing glial cells maintain differentiated
properties including complex morphology and functional synapses. Proc Natl Acad Sci
USA 106: 328 –333, 2009.
718
Physiol Rev • VOL 95 • JULY 2015 • www.prv.org
NEUROGLIAL TRANSMISSION
137. Gertig U, Hanisch UK. Microglial diversity by responses and responders. Front Cell
Neurosci 8: 101, 2014.
138. Glenn TC, Martin NA, Horning MA, McArthur DL, Hovda D, Vespa PM, Brooks GA.
Lactate: brain fuel in human traumatic brain injury. A comparison to normal healthy
control subjects. J Neurotrauma. In press.
139. Goldmann T, Tay TL, Prinz M. Love and death: microglia, NLRP3 and the Alzheimer’s
brain. Cell Res 23: 595–596, 2013.
140. Goldmann T, Tay TL, Prinz M. Love and death: microglia, NLRP3 and the Alzheimer’s
brain. Cell Res 23: 595–596, 2013.
141. Görg B, Morwinsky A, Keitel V, Qvartskhava N, Schror K, Haussinger D. Ammonia
triggers exocytotic release of L-glutamate from cultured rat astrocytes. Glia 58: 691–
705, 2010.
142. Gourine AV, Kasymov V, Marina N, Tang F, Figueiredo MF, Lane S, Teschemacher
AG, Spyer KM, Deisseroth K, Kasparov S. Astrocytes control breathing through pHdependent release of ATP. Science 329: 571–575, 2010.
143. Grosche J, Matyash V, Moller T, Verkhratsky A, Reichenbach A, Kettenmann H.
Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial
cells. Nat Neurosci 2: 139 –143, 1999.
144. Grydeland H, Walhovd KB, Tamnes CK, Westlye LT, Fjell AM. Intracortical myelin
links with performance variability across the human lifespan: results from T1- and
T2-weighted MRI myelin mapping and diffusion tensor imaging. J Neurosci 33: 18618 –
18630, 2013.
145. Hagino Y, Kariura Y, Manago Y, Amano T, Wang B, Sekiguchi M, Nishikawa K, Aoki S,
Wada K, Noda M. Heterogeneity and potentiation of AMPA type of glutamate receptors in rat cultured microglia. Glia 47: 68 –77, 2004.
146. Halassa MM, Florian C, Fellin T, Munoz JR, Lee SY, Abel T, Haydon PG, Frank MG.
Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss.
Neuron 61: 213–219, 2009.
147. Halestrap AP. The SLC16 gene family: structure, role and regulation in health and
disease. Mol Aspects Med 34: 337–349, 2013.
148. Hamilton NB, Attwell D. Do astrocytes really exocytose neurotransmitters? Nat Rev
Neurosci 11: 227–238, 2010.
149. Han J, Kesner P, Metna-Laurent M, Duan T, Xu L, Georges F, Koehl M, Abrous DN,
Mendizabal-Zubiaga J, Grandes P, Liu Q, Bai G, Wang W, Xiong L, Ren W, Marsicano
G, Zhang X. Acute cannabinoids impair working memory through astroglial CB1
receptor modulation of hippocampal LTD. Cell 148: 1039 –1050, 2012.
158. Hayashi Y, Ishibashi H, Hashimoto K, Nakanishi H. Potentiation of the NMDA receptor-mediated responses through the activation of the glycine site by microglia secreting soluble factors. Glia 53: 660 – 668, 2006.
159. Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, Julius D. The
P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9: 1512–1519, 2006.
160. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep
A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT.
NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1
mice. Nature 493: 674 – 678, 2013.
161. Henneberger C, Papouin T, Oliet SH, Rusakov DA. Long-term potentiation depends
on release of D-serine from astrocytes. Nature 463: 232–236, 2010.
162. Herculano-Houzel S. The glia/neuron ratio: how it varies uniformly across brain structures and species and what that means for brain physiology and evolution. Glia 62:
1377–1391, 2014.
163. Hertz L, Peng L, Dienel GA. Energy metabolism in astrocytes: high rate of oxidative
metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. J Cereb
Blood Flow Metab 27: 219 –249, 2007.
164. Higashi Y, Segawa S, Matsuo T, Nakamura S, Kikkawa Y, Nishida K, Nagasawa K.
Microglial zinc uptake via zinc transporters induces ATP release and the activation of
microglia. Glia 59: 1933–1945, 2011.
165. Hirayama M, Kuriyama M. MK-801 is cytotoxic to microglia in vitro and its cytotoxicity
is attenuated by glutamate, other excitotoxic agents and atropine. Possible presence
of glutamate receptor and muscarinic receptor on microglia. Brain Res 897: 204 –206,
2001.
166. Höltje M, Hofmann F, Lux R, Veh RW, Just I, Ahnert-Hilger G. Glutamate uptake and
release by astrocytes are enhanced by Clostridium botulinum C3 protein. J Biol Chem
283: 9289 –9299, 2008.
167. Honda S, Sasaki Y, Ohsawa K, Imai Y, Nakamura Y, Inoue K, Kohsaka S. Extracellular
ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y
receptors. J Neurosci 21: 1975–1982, 2001.
168. Hoque R, Farooq A, Ghani A, Gorelick F, Mehal WZ. Lactate reduces liver and
pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via
GPR81-mediated suppression of innate immunity. Gastroenterology 146: 1763–1774,
2014.
170. Horch HW. Local effects of BDNF on dendritic growth. Rev Neurosci 15: 117–129,
2004.
150. Han KS, Woo J, Park H, Yoon BJ, Choi S, Lee CJ. Channel-mediated astrocytic
glutamate release via Bestrophin-1 targets synaptic NMDARs. Mol Brain 6: 4, 2013.
171. Huang Y, Grinspan JB, Abrams CK, Scherer SS. Pannexin1 is expressed by neurons
and glia but does not form functional gap junctions. Glia 55: 46 –56, 2007.
151. Han X, Chen M, Wang F, Windrem M, Wang S, Shanz S, Xu Q, Oberheim NA, Bekar
L, Betstadt S, Silva AJ, Takano T, Goldman SA, Nedergaard M. Forebrain engraftment
by human glial progenitor cells enhances synaptic plasticity and learning in adult mice.
Cell Stem Cell 12: 342–353, 2013.
172. Iglesias R, Dahl G, Qiu F, Spray DC, Scemes E. Pannexin 1: the molecular substrate of
astrocyte “hemichannels.” J Neurosci 29: 7092–7097, 2009.
173. Inoue K. Microglial activation by purines and pyrimidines. Glia 40: 156 –163, 2002.
152. Harada M, Okuda C, Sawa T, Murakami T. Cerebral extracellular glucose and lactate
concentrations during and after moderate hypoxia in glucose- and saline-infused rats.
Anesthesiology 77: 728 –734, 1992.
174. Insel PA, Zhang L, Murray F, Yokouchi H, Zambon AC. Cyclic AMP is both a
pro-apoptotic and anti-apoptotic second messenger. Acta Physiol 204: 277–287,
2012.
153. Harris JJ, Jolivet R, Attwell D. Synaptic energy use and supply. Neuron 75: 762–777,
2012.
175. Jackson JG, O’Donnell JC, Takano H, Coulter DA, Robinson MB. Neuronal activity
and glutamate uptake decrease mitochondrial mobility in astrocytes and position
mitochondria near glutamate transporters. J Neurosci 34: 1613–1624, 2014.
154. Harris KM, Weinberg RJ. Ultrastructure of synapses in the mammalian brain. Cold
Spring Harb Perspect Biol 4: 2012.
176. James G, Butt AM. P2Y and P2X purinoceptor mediated Ca2⫹ signalling in glial cell
pathology in the central nervous system. Eur J Pharmacol 447: 247–260, 2002.
155. Hashimoto T, Hussien R, Oommen S, Gohil K, Brooks GA. Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis.
FASEB J 21: 2602–2612, 2007.
177. Jeftinija SD, Jeftinija KV, Stefanovic G. Cultured astrocytes express proteins involved
in vesicular glutamate release. Brain Res 750: 41– 47, 1997.
156. Haskew-Layton RE, Mongin AA, Kimelberg HK. Hydrogen peroxide potentiates volume-sensitive excitatory amino acid release via a mechanism involving Ca2⫹/calmodulin-dependent protein kinase II. J Biol Chem 280: 3548 –3554, 2005.
178. Jiang S, Yuan H, Duan L, Cao R, Gao B, Xiong YF, Rao ZR. Glutamate release through
connexin 43 by cultured astrocytes in a stimulated hypertonicity model. Brain Res
1392: 8 –15, 2011.
157. Haskew-Layton RE, Rudkouskaya A, Jin Y, Feustel PJ, Kimelberg HK, Mongin AA. Two
distinct modes of hypoosmotic medium-induced release of excitatory amino acids and
taurine in the rat brain in vivo. PLoS One 3: e3543, 2008.
179. Jourdain P, Bergersen LH, Bhaukaurally K, Bezzi P, Santello M, Domercq M, Matute
C, Tonello F, Gundersen V, Volterra A. Glutamate exocytosis from astrocytes controls synaptic strength. Nat Neurosci 10: 331–339, 2007.
Physiol Rev • VOL 95 • JULY 2015 • www.prv.org
719
GUNDERSEN ET AL.
180. Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A, Littman DR.
Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green
fluorescent protein reporter gene insertion. Mol Cell Biol 20: 4106 – 4114, 2000.
181. Kaindl AM, Degos V, Peineau S, Gouadon E, Chhor V, Loron G, Le CT, Josserand J, Ali
C, Vivien D, Collingridge GL, Lombet A, Issa L, Rene F, Loeffler JP, Kavelaars A,
Verney C, Mantz J, Gressens P. Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain.
Ann Neurol 72: 536 –549, 2012.
182. Kang J, Jiang L, Goldman SA, Nedergaard M. Astrocyte-mediated potentiation of
inhibitory synaptic transmission. Nat Neurosci 1: 683– 692, 1998.
202. Kozlov AS, Angulo MC, Audinat E, Charpak S. Target cell-specific modulation of
neuronal activity by astrocytes. Proc Natl Acad Sci USA 103: 10058 –10063, 2006.
203. Krabbe G, Matyash V, Pannasch U, Mamer L, Boddeke HW, Kettenmann H.
Activation of serotonin receptors promotes microglial injury-induced motility but
attenuates phagocytic activity. Brain Behav Immun 26: 419 – 428,
2012.
204. Kreft M, Stenovec M, Rupnik M, Grilc S, Krzan M, Potokar M, Pangrsic T, Haydon PG,
Zorec R. Properties of Ca2⫹-dependent exocytosis in cultured astrocytes. Glia 46:
437– 445, 2004.
183. Kang J, Kang N, Lovatt D, Torres A, Zhao Z, Lin J, Nedergaard M. Connexin 43
hemichannels are permeable to ATP. J Neurosci 28: 4702– 4711, 2008.
205. Kuhn SA, van Landeghem FK, Zacharias R, Farber K, Rappert A, Pavlovic S, Hoffmann
A, Nolte C, Kettenmann H. Microglia express GABA(B) receptors to modulate interleukin release. Mol Cell Neurosci 25: 312–322, 2004.
184. Kang N, Peng H, Yu Y, Stanton PK, Guilarte TR, Kang J. Astrocytes release D-serine by
a large vesicle. Neuroscience 240: 243–257, 2013.
206. Kukley M, Capetillo-Zarate E, Dietrich D. Vesicular glutamate release from axons in
white matter. Nat Neurosci 10: 311–320, 2007.
185. Kanno T, Nishizaki T. A2a adenosine receptor mediates PKA-dependent glutamate
release from synaptic-like vesicles and Ca2⫹ efflux from an IP3- and ryanodine-insensitive intracellular calcium store in astrocytes. Cell Physiol Biochem 30: 1398 –1412,
2012.
207. Kukley M, Kiladze M, Tognatta R, Hans M, Swandulla D, Schramm J, Dietrich D. Glial
cells are born with synapses. FASEB J 22: 2957–2969, 2008.
186. Káradóttir R, Cavelier P, Bergersen LH, Attwell D. NMDA receptors are expressed in
oligodendrocytes and activated in ischaemia. Nature 438: 1162–1166, 2005.
187. Káradóttir R, Hamilton NB, Bakiri Y, Attwell D. Spiking and nonspiking classes of
oligodendrocyte precursor glia in CNS white matter. Nat Neurosci 11: 450 – 456,
2008.
188. Kato K, Evans AM, Kozlowski RZ. Relaxation of endothelin-1-induced pulmonary
arterial constriction by niflumic acid and NPPB: mechanism(s) independent of chloride channel block. J Pharmacol Exp Ther 288: 1242–1250, 1999.
189. Kaufman AM, Milnerwood AJ, Sepers MD, Coquinco A, She K, Wang L, Lee H, Craig
AM, Cynader M, Raymond LA. Opposing roles of synaptic and extrasynaptic NMDA
receptor signaling in cocultured striatal and cortical neurons. J Neurosci 32: 3992–
4003, 2012.
190. Kettenmann H, Ransom BR. Neuroglia. Oxford: Oxford Univ. Press, 2013.
191. Kettenmann H, Hanisch UK, Noda MF, Verkhratsky A. Physiology of microglia. Physiol
Rev 91: 461–553, 2011.
208. Kukley M, Nishiyama A, Dietrich D. The fate of synaptic input to NG2 glial cells:
neurons specifically downregulate transmitter release onto differentiating oligodendroglial cells. J Neurosci 30: 8320 – 8331, 2010.
209. Kuo YH, Abdullaev IF, Hyzinski-Garcia MC, Mongin AA. Effects of alternative splicing
on the function of bestrophin-1 calcium-activated chloride channels. Biochem J 458:
575–583, 2014.
210. Lalo U, Palygin O, Rasooli-Nejad S, Andrew J, Haydon PG, Pankratov Y. Exocytosis of
ATP from astrocytes modulates phasic and tonic inhibition in the neocortex. PLoS Biol
12: e1001747, 2014.
211. Lalo U, Pankratov Y, Kirchhoff F, North RA, Verkhratsky A. NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes. J Neurosci 26: 2673–2683,
2006.
212. Larsson M, Sawada K, Morland C, Hiasa M, Ormel L, Moriyama Y, Gundersen V.
Functional and anatomical identification of a vesicular transporter mediating neuronal
ATP release. Cereb Cortex 22: 1203–1214, 2012.
192. Kettenmann H, Verkhratsky A. Neuroglia: the 150 years after. Trends Neurosci 31:
653– 659, 2008.
213. Lauritzen KH, Morland C, Puchades M, Holm-Hansen S, Hagelin EM, Lauritzen F,
Attramadal H, Storm-Mathisen J, Gjedde A, Bergersen LH. Lactate receptor sites link
neurotransmission, neurovascular coupling, and brain energy metabolism. Cereb Cortex 24: 2784 –2795, 2014. [Epub 21 May 2013].
193. Kimelberg HK, Goderie SK, Higman S, Pang S, Waniewski RA. Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures. J Neurosci 10:
1583–1591, 1990.
214. Lavialle M, Aumann G, Anlauf E, Prols F, Arpin M, Derouiche A. Structural plasticity of
perisynaptic astrocyte processes involves ezrin and metabotropic glutamate receptors. Proc Natl Acad Sci USA 108: 12915–12919, 2011.
194. Kimelberg HK, MacVicar BA, Sontheimer H. Anion channels in astrocytes: biophysics,
pharmacology, and function. Glia 54: 747–757, 2006.
215. Le DH, Kwon YK. A coherent feedforward loop design principle to sustain robustness
of biological networks. Bioinformatics 29: 630 – 637, 2013.
195. Kirchhoff F, Kettenmann H. GABA triggers a [Ca2⫹]i increase in murine precursor
cells of the oligodendrocyte lineage. Eur J Neurosci 4: 1049 –1058, 1992.
216. Leal G, Afonso PM, Salazar IL, Duarte CB. Regulation of hippocampal synaptic plasticity by BDNF. Brain Res 2014; doi:10.1016/j.brainres.2014.10.019.
196. Kirkup AJ, Edwards G, Weston AH. Investigation of the effects of 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) on membrane currents in rat portal vein. Br J
Pharmacol 117: 175–183, 1996.
217. Lee IS, Kim KJ, Kang EH, Yu BH. Beta-adrenoceptor affinity as a biological predictor of
treatment response to paroxetine in patients with acute panic disorder. J Affect Disord
110: 156 –160, 2008.
197. Kirov SA, Sorra KE, Harris KM. Slices have more synapses than perfusion-fixed hippocampus from both young and mature rats. J Neurosci 19: 2876 –2886, 1999.
218. Lee S, Yoon BE, Berglund K, Oh SJ, Park H, Shin HS, Augustine GJ, Lee CJ. Channelmediated tonic GABA release from glia. Science 330: 790 –796, 2010.
198. Koizumi S. Synchronization of Ca2⫹ oscillations: involvement of ATP release in astrocytes. FEBS J 277: 286 –292, 2010.
219. Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, Liu Y, Tsingalia
A, Jin L, Zhang PW, Pellerin L, Magistretti PJ, Rothstein JD. Oligodendroglia
metabolically support axons and contribute to neurodegeneration. Nature 487:
443– 448, 2012.
199. Koizumi S, Fujishita K, Tsuda M, Shigemoto-Mogami Y, Inoue K. Dynamic inhibition of
excitatory synaptic transmission by astrocyte-derived ATP in hippocampal cultures.
Proc Natl Acad Sci USA 100: 11023–11028, 2003.
220. Leonard BE. A study of the neurohumoral control of glycolysis in the mouse brain in
vivo: role of noradrenaline and dopamine. Z Naturforsch C 30: 385–391, 1975.
200. Koizumi S, Ohsawa K, Inoue K, Kohsaka S. Purinergic receptors in microglia: functional modal shifts of microglia mediated by P2 and P1 receptors. Glia 61: 47–54,
2013.
221. Lewitus GM, Pribiag H, Duseja R, St-Hilaire M, Stellwagen D. An adaptive role of
TNFalpha in the regulation of striatal synapses. J Neurosci 34: 6146 – 6155, 2014.
201. Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M,
Joshi BV, Jacobson KA, Kohsaka S, Inoue K. UDP acting at P2Y6 receptors is a
mediator of microglial phagocytosis. Nature 446: 1091–1095, 2007.
222. Li D, Herault K, Silm K, Evrard A, Wojcik S, Oheim M, Herzog E, Ropert N. Lack of
evidence for vesicular glutamate transporter expression in mouse astrocytes. J Neurosci 33: 4434 – 4455, 2013.
720
Physiol Rev • VOL 95 • JULY 2015 • www.prv.org
NEUROGLIAL TRANSMISSION
223. Li D, Ropert N, Koulakoff A, Giaume C, Oheim M. Lysosomes are the major vesicular
compartment undergoing Ca2⫹-regulated exocytosis from cortical astrocytes. J Neurosci 28: 7648 –7658, 2008.
243. Ma W, Compan V, Zheng W, Martin E, North RA, Verkhratsky A, Surprenant A.
Pannexin 1 forms an anion-selective channel. Pflügers Arch 463: 585–592, 2012.
224. Li G, Wang HQ, Wang LH, Chen RP, Liu JP. Distinct pathways of ERK1/2 activation by
hydroxy-carboxylic acid receptor-1. PLoS One 9: e93041, 2014.
244. Maddock RJ, Buonocore MH, Copeland LE, Richards AL. Elevated brain lactate responses to neural activation in panic disorder: a dynamic 1H-MRS study. Mol Psychiatry
14: 537–545, 2009.
225. Li S, Mealing GA, Morley P, Stys PK. Novel injury mechanism in anoxia and trauma of
spinal cord white matter: glutamate release via reverse Na⫹-dependent glutamate
transport. J Neurosci 19: RC16, 1999.
245. Maekawa F, Minehira K, Kadomatsu K, Pellerin L. Basal and stimulated lactate fluxes
in primary cultures of astrocytes are differentially controlled by distinct proteins. J
Neurochem 107: 789 –798, 2008.
226. Li Z, Okamoto K, Hayashi Y, Sheng M. The importance of dendritic mitochondria in
the morphogenesis and plasticity of spines and synapses. Cell 119: 873– 887, 2004.
246. Makani S, Chesler M. Endogenous alkaline transients boost postsynaptic NMDA receptor responses in hippocampal CA1 pyramidal neurons. J Neurosci 27: 7438 –7446,
2007.
227. Lin SC, Bergles DE. Synaptic signaling between GABAergic interneurons and oligodendrocyte precursor cells in the hippocampus. Nat Neurosci 7: 24 –32, 2004.
228. Lin YC, Yeckel MF, Koleske AJ. Abl2/Arg controls dendritic spine and dendrite arbor
stability via distinct cytoskeletal control pathways. J Neurosci 33: 1846 –1857, 2013.
229. Linnertz R, Wurm A, Pannicke T, Krugel K, Hollborn M, Hartig W, Iandiev I, Wiedemann P, Reichenbach A, Bringmann A. Activation of voltage-gated Na⫹ and Ca2⫹
channels is required for glutamate release from retinal glial cells implicated in cell
volume regulation. Neuroscience 188: 23–34, 2011.
230. Liu C, Kuei C, Zhu J, Yu J, Zhang L, Shih A, Mirzadegan T, Shelton J, Sutton S, Connelly
MA, Lee G, Carruthers N, Wu J, Lovenberg TW. 3,5-Dihydroxybenzoic acid, a specific agonist for hydroxycarboxylic acid 1, inhibits lipolysis in adipocytes. J Pharmacol
Exp Ther 341: 794 – 801, 2012.
231. Liu C, Wu J, Zhu J, Kuei C, Yu J, Shelton J, Sutton SW, Li X, Yun SJ, Mirzadegan T,
Mazur C, Kamme F, Lovenberg TW. Lactate inhibits lipolysis in fat cells through
activation of an orphan G-protein-coupled receptor, GPR81. J Biol Chem 284: 2811–
2822, 2009.
247. Makani S, Chesler M. Endogenous alkaline transients boost postsynaptic NMDA receptor responses in hippocampal CA1 pyramidal neurons. J Neurosci 27: 7438 –7446,
2007.
248. Malarkey EB, Parpura V. Temporal characteristics of vesicular fusion in astrocytes:
examination of synaptobrevin 2-laden vesicles at single vesicle resolution. J Physiol
589: 4271– 4300, 2011.
249. Manning SM, Talos DM, Zhou C, Selip DB, Park HK, Park CJ, Volpe JJ, Jensen FE.
NMDA receptor blockade with memantine attenuates white matter injury in a rat
model of periventricular leukomalacia. J Neurosci 28: 6670 – 6678, 2008.
250. Marchaland J, Cali C, Voglmaier SM, Li H, Regazzi R, Edwards RH, Bezzi P. Fast
subplasma membrane Ca2⫹ transients control exo-endocytosis of synaptic-like microvesicles in astrocytes. J Neurosci 28: 9122–9132, 2008.
251. Marcourakis T, Gorenstein C, Brandao de Almeida PE, Ramos RT, Glezer I, Bernardes
CS, Kawamoto EM, Scavone C. Panic disorder patients have reduced cyclic AMP in
platelets. J Psychiatr Res 36: 105–110, 2002.
232. Liu HT, Akita T, Shimizu T, Sabirov RZ, Okada Y. Bradykinin-induced astrocyteneuron signalling: glutamate release is mediated by ROS-activated volume-sensitive
outwardly rectifying anion channels. J Physiol 587: 2197–2209, 2009.
252. Martineau M, Galli T, Baux G, Mothet JP. Confocal imaging and tracking of the exocytotic routes for D-serine-mediated gliotransmission. Glia 56: 1271–1284, 2008.
233. Liu HT, Tashmukhamedov BA, Inoue H, Okada Y, Sabirov RZ. Roles of two types of
anion channels in glutamate release from mouse astrocytes under ischemic or osmotic
stress. Glia 54: 343–357, 2006.
253. Martineau M, Shi T, Puyal J, Knolhoff AM, Dulong J, Gasnier B, Klingauf J, Sweedler JV,
Jahn R, Mothet JP. Storage and uptake of D-serine into astrocytic synaptic-like vesicles
specify gliotransmission. J Neurosci 33: 3413–3423, 2013.
234. Liu L, Chan C. The role of inflammasome in Alzheimer’s disease. Ageing Res Rev 15:
6 –15, 2014.
254. Matsui K, Jahr CE, Rubio ME. High-concentration rapid transients of glutamate mediate neural-glial communication via ectopic release. J Neurosci 25: 7538 –7547, 2005.
235. Liu QS, Xu Q, Arcuino G, Kang J, Nedergaard M. Astrocyte-mediated activation of
neuronal kainate receptors. Proc Natl Acad Sci USA 101: 3172–3177, 2004.
255. Matthias K, Kirchhoff F, Seifert G, Huttmann K, Matyash M, Kettenmann H, Steinhauser C. Segregated expression of AMPA-type glutamate receptors and glutamate
transporters defines distinct astrocyte populations in the mouse hippocampus. J Neurosci 23: 1750 –1758, 2003.
236. Liu T, Sun L, Xiong Y, Shang S, Guo N, Teng S, Wang Y, Liu B, Wang C, Wang L, Zheng
L, Zhang CX, Han W, Zhou Z. Calcium triggers exocytosis from two types of organelles in a single astrocyte. J Neurosci 31: 10593–10601, 2011.
237. Liu X, Betzenhauser MJ, Reiken S, Meli AC, Xie W, Chen BX, Arancio O, Marks AR.
Role of leaky neuronal ryanodine receptors in stress-induced cognitive dysfunction.
Cell 150: 1055–1067, 2012.
238. Loane DJ, Stoica BA, Pajoohesh-Ganji A, Byrnes KR, Faden AI. Activation of metabotropic glutamate receptor 5 modulates microglial reactivity and neurotoxicity by
inhibiting NADPH oxidase. J Biol Chem 284: 15629 –15639, 2009.
239. Lovatt D, Sonnewald U, Waagepetersen HS, Schousboe A, He W, Lin JH, Han X,
Takano T, Wang S, Sim FJ, Goldman SA, Nedergaard M. The transcriptome and
metabolic gene signature of protoplasmic astrocytes in the adult murine cortex. J
Neurosci 27: 12255–12266, 2007.
240. Lovatt D, Sonnewald U, Waagepetersen HS, Schousboe A, He W, Lin JH, Han X,
Takano T, Wang S, Sim FJ, Goldman SA, Nedergaard M. The transcriptome and
metabolic gene signature of protoplasmic astrocytes in the adult murine cortex. J
Neurosci 27: 12255–12266, 2007.
256. Matute C. Oligodendrocyte NMDA receptors: a novel therapeutic target. Trends Mol
Med 12: 289 –292, 2006.
257. Matute C, Sanchez-Gomez MV, Martinez-Millan L, Miledi R. Glutamate receptormediated toxicity in optic nerve oligodendrocytes. Proc Natl Acad Sci USA 94: 8830 –
8835, 1997.
258. McBrian MA, Behbahan IS, Ferrari R, Su T, Huang TW, Li K, Hong CS, Christofk HR,
Vogelauer M, Seligson DB, Kurdistani SK. Histone acetylation regulates intracellular
pH. Mol Cell 49: 310 –321, 2013.
259. McMullan SM, Phanavanh B, Li GG, Barger SW. Metabotropic glutamate receptors
inhibit microglial glutamate release. ASN Neuro 4: 2012.
260. Medina JM, Tabernero A. Lactate utilization by brain cells and its role in CNS development. J Neurosci Res 79: 2–10, 2005.
261. Micu I, Jiang Q, Coderre E, Ridsdale A, Zhang L, Woulfe J, Yin X, Trapp BD, McRory
JE, Rehak R, Zamponi GW, Wang W, Stys PK. NMDA receptors mediate calcium
accumulation in myelin during chemical ischaemia. Nature 439: 988 –992, 2006.
241. Lundgaard I, Luzhynskaya A, Stockley JH, Wang Z, Evans KA, Swire M, Volbracht K,
Gautier HO, Franklin RJ, Attwell D, Karadottir RT. Neuregulin and BDNF induce a
switch to NMDA receptor-dependent myelination by oligodendrocytes. PLoS Biol 11:
e1001743, 2013.
262. Micu I, Ridsdale A, Zhang L, Woulfe J, McClintock J, Brantner CA, Andrews SB, Stys
PK. Real-time measurement of free Ca2⫹ changes in CNS myelin by two-photon
microscopy. Nat Med 13: 874 – 879, 2007.
242. Luyt K, Slade TP, Dorward JJ, Durant CF, Wu Y, Shigemoto R, Mundell SJ, Varadi A,
Molnar E. Developing oligodendrocytes express functional GABA(B) receptors that
stimulate cell proliferation and migration. J Neurochem 100: 822– 840, 2007.
263. Mintun MA, Vlassenko AG, Rundle MM, Raichle ME. Increased lactate/pyruvate ratio
augments blood flow in physiologically activated human brain. Proc Natl Acad Sci USA
101: 659 – 664, 2004.
Physiol Rev • VOL 95 • JULY 2015 • www.prv.org
721
GUNDERSEN ET AL.
264. Mizutani M, Pino PA, Saederup N, Charo IF, Ransohoff RM, Cardona AE. The fractalkine receptor but not CCR2 is present on microglia from embryonic development
throughout adulthood. J Immunol 188: 29 –36, 2012.
265. Molokanova E, Akhtar MW, Sanz-Blasco S, Tu S, Pina-Crespo JC, McKercher SR,
Lipton SA. Differential effects of synaptic and extrasynaptic NMDA receptors on
Abeta-induced nitric oxide production in cerebrocortical neurons. J Neurosci 34:
5023–5028, 2014.
266. Mongin AA, Kimelberg HK. ATP potently modulates anion channel-mediated excitatory amino acid release from cultured astrocytes. Am J Physiol Cell Physiol 283:
C569 –C578, 2002.
267. Mongin AA, Kimelberg HK. ATP regulates anion channel-mediated organic osmolyte
release from cultured rat astrocytes via multiple Ca2⫹-sensitive mechanisms. Am J
Physiol Cell Physiol 288: C204 –C213, 2005.
268. Montana V, Ni Y, Sunjara V, Hua X, Parpura V. Vesicular glutamate transporterdependent glutamate release from astrocytes. J Neurosci 24: 2633–2642, 2004.
270. Montero TD, Orellana JA. Hemichannels: new pathways for gliotransmitter release.
Neuroscience 286C: 45–59, 2015.
271. Mookerjee SA, Goncalves RL, Gerencser AA, Nicholls DG, Brand MD. The contributions of respiration and glycolysis to extracellular acid production. Biochim Biophys
Acta 1847: 171–181, 2015.
272. Moriguchi S, Mizoguchi Y, Tomimatsu Y, Hayashi Y, Kadowaki T, Kagamiishi Y, Katsube N, Yamamoto K, Inoue K, Watanabe S, Nabekura J, Nakanishi H. Potentiation of
NMDA receptor-mediated synaptic responses by microglia. Brain Res Mol Brain Res
119: 160 –169, 2003.
273. Mott DD, Washburn MS, Zhang S, Dingledine RJ. Subunit-dependent modulation of
kainate receptors by extracellular protons and polyamines. J Neurosci 23: 1179 –1188,
2003.
274. Nafstad PH, Blackstad TW. Distribution of mitochondria in pyramidal cells and boutons in hippocampal cortex. Z Zellforsch Mikrosk Anat 73: 234 –245, 1966.
275. Nagase M, Takahashi Y, Watabe AM, Kubo Y, Kato F. On-site energy supply at
synapses through monocarboxylate transporters maintains excitatory synaptic transmission. J Neurosci 34: 2605–2617, 2014.
276. Nakamura M, Bhatnagar A, Sadoshima J. Overview of pyridine nucleotides review
series. Circ Res 111: 604 – 610, 2012.
277. Nakase T, Fushiki S, Naus CC. Astrocytic gap junctions composed of connexin 43
reduce apoptotic neuronal damage in cerebral ischemia. Stroke 34: 1987–1993, 2003.
278. Nakase T, Sohl G, Theis M, Willecke K, Naus CC. Increased apoptosis and inflammation after focal brain ischemia in mice lacking connexin43 in astrocytes. Am J Pathol
164: 2067–2075, 2004.
279. Navarrete M, Araque A. Endocannabinoids mediate neuron-astrocyte communication. Neuron 57: 883– 893, 2008.
280. Navarrete M, Perea G, Fernandez de SD, Gomez-Gonzalo M, Nunez A, Martin ED,
Araque A. Astrocytes mediate in vivo cholinergic-induced synaptic plasticity. PLoS Biol
10: e1001259, 2012.
281. Navarrete M, Perea G, Maglio L, Pastor J, Garcia de SR, Araque A. Astrocyte calcium
signal and gliotransmission in human brain tissue. Cereb Cortex 23: 1240 –1246, 2013.
282. Nave KA. Myelination and the trophic support of long axons. Nat Rev Neurosci 11:
275–283, 2010.
283. Ni Y, Parpura V. Dual regulation of Ca2⫹-dependent glutamate release from astrocytes: vesicular glutamate transporters and cytosolic glutamate levels. Glia 57: 1296 –
1305, 2009.
284. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic
surveillants of brain parenchyma in vivo. Science 308: 1314 –1318, 2005.
288. Nordengen K, Heuser C, Rinholm JE, Matalon R, Gundersen V. Localisation of Nacetylaspartate in oligodendrocytes/myelin. Brain Struct Funct 220: 899 –917, 2015.
289. Nörenberg W, Langosch JM, Gebicke-Haerter PJ, Illes P. Characterization and possible function of adenosine 5’-triphosphate receptors in activated rat microglia. Br J
Pharmacol 111: 942–950, 1994.
290. O’Carroll SJ, Gorrie CA, Velamoor S, Green CR, Nicholson LF. Connexin43 mimetic
peptide is neuroprotective and improves function following spinal cord injury. Neurosci Res 75: 256 –267, 2013.
291. Ogata K, Kosaka T. Structural and quantitative analysis of astrocytes in the mouse
hippocampus. Neuroscience 113: 221–233, 2002.
292. Ohsawa K, Irino Y, Nakamura Y, Akazawa C, Inoue K, Kohsaka S. Involvement of
P2X4 and P2Y12 receptors in ATP-induced microglial chemotaxis. Glia 55: 604 – 616,
2007.
293. Ohsawa K, Irino Y, Sanagi T, Nakamura Y, Suzuki E, Inoue K, Kohsaka S. P2Y12
receptor-mediated integrin-beta1 activation regulates microglial process extension
induced by ATP. Glia 58: 790 – 801, 2010.
294. Oliveira JF, Riedel T, Leichsenring A, Heine C, Franke H, Krugel U, Norenberg W, Illes
P. Rodent cortical astroglia express in situ functional P2X7 receptors sensing pathologically high ATP concentrations. Cereb Cortex 21: 806 – 820, 2011.
295. Ormel L, Stensrud MJ, Bergersen LH, Gundersen V. VGLUT1 is localized in astrocytic
processes in several brain regions. Glia 60: 229 –238, 2012.
296. Ormel L, Stensrud MJ, Chaudhry FA, Gundersen V. A distinct set of synaptic-like
microvesicles in atroglial cells contain VGLUT3. Glia 60: 1289 –1300, 2012.
297. Ottersen OP, Madsen S, Storm-Mathisen J, Somogyi P, Scopsi L, Larsson LI. Immunocytochemical evidence suggests that taurine is colocalized with GABA in the Purkinje cell terminals, but that the stellate cell terminals predominantly contain GABA: a
light- and electronmicroscopic study of the rat cerebellum. Exp Brain Res 72: 407–
416, 1988.
298. Ouardouz M, Coderre E, Basak A, Chen A, Zamponi GW, Hameed S, Rehak R, Yin X,
Trapp BD, Stys PK. Glutamate receptors on myelinated spinal cord axons. I. GluR6
kainate receptors. Ann Neurol 65: 151–159, 2009.
299. Ouardouz M, Coderre E, Zamponi GW, Hameed S, Yin X, Trapp BD, Stys PK.
Glutamate receptors on myelinated spinal cord axons. II. AMPA and GluR5 receptors.
Ann Neurol 65: 160 –166, 2009.
300. Overgaard M, Rasmussen P, Bohm AM, Seifert T, Brassard P, Zaar M, Homann P,
Evans KA, Nielsen HB, Secher NH. Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain. FASEB J 26: 3012–3020, 2012.
301. Oya M, Kitaguchi T, Yanagihara Y, Numano R, Kakeyama M, Ikematsu K, Tsuboi T.
Vesicular nucleotide transporter is involved in ATP storage of secretory lysosomes in
astrocytes. Biochem Biophys Res Commun 438: 145–151, 2013.
302. Ozaki M, Itoh K, Miyakawa Y, Kishida H, Hashikawa T. Protein processing and releases of neuregulin-1 are regulated in an activity-dependent manner. J Neurochem 91:
176 –188, 2004.
303. Palygin O, Lalo U, Verkhratsky A, Pankratov Y. Ionotropic NMDA and P2X1/5 receptors mediate synaptically induced Ca2⫹ signalling in cortical astrocytes. Cell Calcium 48: 225–231, 2010.
304. Panatier A, Theodosis DT, Mothet JP, Touquet B, Pollegioni L, Poulain DA, Oliet SH.
Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell
125: 775–784, 2006.
305. Panatier A, Vallee J, Haber M, Murai KK, Lacaille JC, Robitaille R. Astrocytes are
endogenous regulators of basal transmission at central synapses. Cell 146: 785–798,
2011.
307. Pangrsic T, Potokar M, Stenovec M, Kreft M, Fabbretti E, Nistri A, Pryazhnikov E,
Khiroug L, Giniatullin R, Zorec R. Exocytotic release of ATP from cultured astrocytes.
J Biol Chem 282: 28749 –28758, 2007.
286. Nishiyori A, Minami M, Ohtani Y, Takami S, Yamamoto J, Kawaguchi N, Kume T,
Akaike A, Satoh M. Localization of fractalkine and CX3CR1 mRNAs in rat brain: does
fractalkine play a role in signaling from neuron to microglia? FEBS Lett 429: 167–172,
1998.
307a.Pankratov Y, Lalo U, Verkhratsky A, North RA. Vesicular release of ATP at central
synapses. Pflügers Arch 452: 589 –597, 2006.
287. Noda M, Nakanishi H, Nabekura J, Akaike N. AMPA-kainate subtypes of glutamate
receptor in rat cerebral microglia. J Neurosci 20: 251–258, 2000.
308. Pantoni L, Garcia JH, Gutierrez JA. Cerebral white matter is highly vulnerable to
ischemia. Stroke 27: 1641–1646, 1996.
722
Physiol Rev • VOL 95 • JULY 2015 • www.prv.org
NEUROGLIAL TRANSMISSION
309. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M,
Ferreira TA, Guiducci E, Dumas L, Ragozzino D, Gross CT. Synaptic pruning by
microglia is necessary for normal brain development. Science 333: 1456 –1458, 2011.
331. Petzold GC, Albeanu DF, Sato TF, Murthy VN. Coupling of neural activity to blood
flow in olfactory glomeruli is mediated by astrocytic pathways. Neuron 58: 897–910,
2008.
310. Park H, Han KS, Oh SJ, Jo S, Woo J, Yoon BE, Lee CJ. High glutamate permeability and
distal localization of Best1 channel in CA1 hippocampal astrocyte. Mol Brain 6: 54,
2013.
332. Petzold GC, Murthy VN. Role of astrocytes in neurovascular coupling. Neuron 71:
782–797, 2011.
311. Park H, Oh SJ, Han KS, Woo DH, Park H, Mannaioni G, Traynelis SF, Lee CJ. Bestrophin-1 encodes for the Ca2⫹-activated anion channel in hippocampal astrocytes. J
Neurosci 29: 13063–13073, 2009.
312. Parkerson KA, Sontheimer H. Biophysical and pharmacological characterization of
hypotonically activated chloride currents in cortical astrocytes. Glia 46: 419 – 436,
2004.
333. Platel JC, Dave KA, Gordon V, Lacar B, Rubio ME, Bordey A. NMDA receptors
activated by subventricular zone astrocytic glutamate are critical for neuroblast survival prior to entering a synaptic network. Neuron 65: 859 – 872, 2010.
334. Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci 30: 527–535, 2007.
335. Porter JT, McCarthy KD. Hippocampal astrocytes in situ respond to glutamate released from synaptic terminals. J Neurosci 16: 5073–5081, 1996.
313. Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG. Glutamate-mediated
astrocyte-neuron signalling. Nature 369: 744 –747, 1994.
336. Potokar M, Kreft M, Lee SY, Takano H, Haydon PG, Zorec R. Trafficking of astrocytic
vesicles in hippocampal slices. Biochem Biophys Res Commun 390: 1192–1196, 2009.
314. Parri HR, Gould TM, Crunelli V. Spontaneous astrocytic Ca2⫹ oscillations in situ drive
NMDAR-mediated neuronal excitation. Nat Neurosci 4: 803– 812, 2001.
337. Prinz M, Hausler KG, Kettenmann H, Hanisch U. Beta-adrenergic receptor stimulation selectively inhibits IL-12p40 release in microglia. Brain Res 899: 264 –270, 2001.
315. Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, Takano H, Moss
SJ, McCarthy K, Haydon PG. Astrocytic purinergic signaling coordinates synaptic
networks. Science 310: 113–116, 2005.
338. Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to
neuropsychiatric disease. Nat Rev Neurosci 15: 300 –312, 2014.
316. Paspalas CD, Wang M, Arnsten AF. Constellation of HCN channels and cAMP regulating proteins in dendritic spines of the primate prefrontal cortex: potential substrate
for working memory deficits in schizophrenia. Cereb Cortex 23: 1643–1654, 2013.
317. Passlick S, Grauer M, Schafer C, Jabs R, Seifert G, Steinhauser C. Expression of the
gamma2-subunit distinguishes synaptic and extrasynaptic GABA(A) receptors in NG2
cells of the hippocampus. J Neurosci 33: 12030 –12040, 2013.
318. Pasti L, Volterra A, Pozzan T, Carmignoto G. Intracellular calcium oscillations in
astrocytes: a highly plastic, bidirectional form of communication between neurons
and astrocytes in situ. J Neurosci 17: 7817–7830, 1997.
319. Pasti L, Zonta M, Pozzan T, Vicini S, Carmignoto G. Cytosolic calcium oscillations in
astrocytes may regulate exocytotic release of glutamate. J Neurosci 21: 477– 484,
2001.
320. Pastor A, Chvatal A, Sykova E, Kettenmann H. Glycine- and GABA-activated currents
in identified glial cells of the developing rat spinal cord slice. Eur J Neurosci 7: 1188 –
1198, 1995.
321. Patel AB, Lai JC, Chowdhury GM, Hyder F, Rothman DL, Shulman RG, Behar KL.
Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle. Proc Natl Acad Sci USA 111:
5385–5390, 2014.
322. Paukert M, Agarwal A, Cha J, Doze VA, Kang JU, Bergles DE. Norepinephrine
controls astroglial responsiveness to local circuit activity. Neuron 82: 1263–1270,
2014.
323. Pedersen TH, Nielsen OB, Lamb GD, Stephenson DG. Intracellular acidosis enhances
the excitability of working muscle. Science 305: 1144 –1147, 2004.
324. Pellerin L, Magistretti PJ. Sweet sixteen for ANLS. J Cereb Blood Flow Metab 32:
1152–1166, 2012.
325. Pelvig DP, Pakkenberg H, Stark AK, Pakkenberg B. Neocortical glial cell numbers in
human brains. Neurobiol Aging 29: 1754 –1762, 2008.
326. Peng H, Kang N, Xu J, Stanton PK, Kang J. Two distinct modes of exocytotic fusion
pore expansion in large astrocytic vesicles. J Biol Chem 288: 16872–16881, 2013.
327. Peng L, Guo C, Wang T, Li B, Gu L, Wang Z. Methodological limitations in determining
astrocytic gene expression. Front Endocrinol 4: 176, 2013.
328. Perea G, Araque A. Properties of synaptically evoked astrocyte calcium signal reveal
synaptic information processing by astrocytes. J Neurosci 25: 2192–2203, 2005.
329. Perea G, Araque A. Astrocytes potentiate transmitter release at single hippocampal
synapses. Science 317: 1083–1086, 2007.
330. Peters A, Palay SL, Webster H. The Fine Structure of the Nervous System (3rd ed.). New
York: Oxford Univ. Press, 1991.
339. Pryazhnikov E, Khiroug L. Sub-micromolar increase in [Ca2⫹]i triggers delayed exocytosis of ATP in cultured astrocytes. Glia 56: 38 – 49, 2008.
340. Qu Z, Wei RW, Mann W, Hartzell HC. Two bestrophins cloned from Xenopus laevis
oocytes express Ca2⫹-activated Cl⫺ currents. J Biol Chem 278: 49563– 49572, 2003.
341. Quistorff B, Secher NH, Van Lieshout JJ. Lactate fuels the human brain during exercise. FASEB J 22: 3443–3449, 2008.
342. Rajendran P, Williams DE, Ho E, Dashwood RH. Metabolism as a key to histone
deacetylase inhibition. Crit Rev Biochem Mol Biol 46: 181–199, 2011.
343. Ramamoorthy P, Whim MD. Trafficking and fusion of neuropeptide Y-containing
dense-core granules in astrocytes. J Neurosci 28: 13815–13827, 2008.
344. Ramon y Cajal S. Histology of the Nervous System of Man and Vertebrates, translated
from the French by N. Swanson and L. W. Swanson. New York: Oxford Univ. Press,
1995,.
345. Reiter E, Ahn S, Shukla AK, Lefkowitz RJ. Molecular mechanism of beta-arrestinbiased agonism at seven-transmembrane receptors. Annu Rev Pharmacol Toxicol 52:
179 –197, 2012.
346. Ribeiro PF, Ventura-Antunes L, Gabi M, Mota B, Grinberg LT, Farfel JM, FerrettiRebustini RE, Leite RE, Filho WJ, Herculano-Houzel S. The human cerebral cortex is
neither one nor many: neuronal distribution reveals two quantitatively different zones
in the gray matter, three in the white matter, and explains local variations in cortical
folding. Front Neuroanat 7: 28, 2013.
347. Rinholm JE, Bergersen LH. Neuroscience: the wrap that feeds neurons. Nature 487:
435– 436, 2012.
348. Rinholm JE, Bergersen LH. White matter lactate– does it matter? Neuroscience 276:
109 –116, 2014.
349. Rinholm JE, Hamilton NB, Kessaris N, Richardson WD, Bergersen LH, Attwell D.
Regulation of oligodendrocyte development and myelination by glucose and lactate. J
Neurosci 31: 538 –548, 2011.
350. Robinet C, Pellerin L. Brain-derived neurotrophic factor enhances the hippocampal
expression of key postsynaptic proteins in vivo including the monocarboxylate transporter MCT2. Neuroscience 192: 155–163, 2011.
351. Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM, Grimmig BA,
Weeber EJ, Bickford PC, Gemma C. CX3CR1 deficiency leads to impairment of
hippocampal cognitive function and synaptic plasticity. J Neurosci 31: 16241–16250,
2011.
352. Roig M, Skriver K, Lundbye-Jensen J, Kiens B, Nielsen JB. A single bout of exercise
improves motor memory. PLoS One 7: e44594, 2012.
353. Rubartelli A. DAMP-mediated activation of NLRP3-inflammasome in brain sterile
inflammation: the fine line between healing and neurodegeneration. Front Immunol 5:
99, 2014.
Physiol Rev • VOL 95 • JULY 2015 • www.prv.org
723
GUNDERSEN ET AL.
354. Ruiz-Garcia A, Monsalve E, Novellasdemunt L, Navarro-Sabate A, Manzano A, Rivero
S, Castrillo A, Casado M, Laborda J, Bartrons R, Diaz-Guerra MJ. Cooperation of
adenosine with macrophage Toll-4 receptor agonists leads to increased glycolytic flux
through the enhanced expression of PFKFB3 gene. J Biol Chem 286: 19247–19258,
2011.
377. Shytle RD, Mori T, Townsend K, Vendrame M, Sun N, Zeng J, Ehrhart J, Silver AA,
Sanberg PR, Tan J. Cholinergic modulation of microglial activation by alpha 7 nicotinic
receptors. J Neurochem 89: 337–343, 2004.
378. Siushansian R, Bechberger JF, Cechetto DF, Hachinski VC, Naus CC. Connexin43 null
mutation increases infarct size after stroke. J Comp Neurol 440: 387–394, 2001.
355. Saab AS, Neumeyer A, Jahn HM, Cupido A, Simek AA, Boele HJ, Scheller A, Le MK,
Gotz M, Monyer H, Sprengel R, Rubio ME, Deitmer JW, De Zeeuw CI, Kirchhoff F.
Bergmann glial AMPA receptors are required for fine motor coordination. Science
337: 749 –753, 2012.
379. Sogn CJ, Puchades M, Gundersen V. Rare contacts between synapses and microglial
processes containing high levels of Iba1 and actin–a postembedding immunogold
study in the healthy rat brain. Eur J Neurosci 38: 2030 –2040, 2013.
356. Saab AS, Tzvetanova ID, Nave KA. The role of myelin and oligodendrocytes in axonal
energy metabolism. Curr Opin Neurobiol 23: 1065–1072, 2013.
380. Somogyi P, Halasy K, Somogyi J, Storm-Mathisen J, Ottersen OP. Quantification of
immunogold labelling reveals enrichment of glutamate in mossy and parallel fibre
terminals in cat cerebellum. Neuroscience 19: 1045–1050, 1986.
357. Sakurai T, Davenport R, Stafford S, Grosse J, Ogawa K, Cameron J, Parton L, Sykes A,
Mack S, Bousba S, Parmar A, Harrison D, Dickson L, Leveridge M, Matsui J, Barnes M.
Identification of a novel GPR81-selective agonist that suppresses lipolysis in mice
without cutaneous flushing. Eur J Pharmacol 727: 1–7, 2014.
381. Sosunov AA, Wu X, Tsankova NM, Guilfoyle E, McKhann GM, Goldman JE. Phenotypic heterogeneity and plasticity of isocortical and hippocampal astrocytes in the
human brain. J Neurosci 34: 2285–2298, 2014.
359. Sanchez-Abarca LI, Tabernero A, Medina JM. Oligodendrocytes use lactate as a
source of energy and as a precursor of lipids. Glia 36: 321–329, 2001.
381a.Sotelo-Hitschfeld T, Niemeyer MI, Mächler P, Ruminot I, Lerchundi R, Wyss MT,
Stobart J, Fernández-Moncada I, Valdebenito R, Garrido-Gerter P, Contreras-Baeza
Y, Schneider BL, Aebischer P, Lengacher S, San Martín A, Le Douce J, Bonvento G,
Magistretti PJ, Sepúlveda FV, Weber B, Barros LF. Channel-mediated lactate release
by K⫹-stimulated astrocytes. J Neurosci 35: 4168 – 4178, 2015.
360. Sanchez-Mendoza E, Burguete MC, Castello-Ruiz M, Gonzalez MP, Roncero C, Salom JB, Arce C, Canadas S, Torregrosa G, Alborch E, Oset-Gasque MJ. Transient focal
cerebral ischemia significantly alters not only EAATs but also VGLUTs expression in
rats: relevance of changes in reactive astroglia. J Neurochem 113: 1343–1355, 2010.
382. Stehberg J, Moraga-Amaro R, Salazar C, Becerra A, Echeverria C, Orellana JA, Bultynck G, Ponsaerts R, Leybaert L, Simon F, Saez JC, Retamal MA. Release of gliotransmitters through astroglial connexin 43 hemichannels is necessary for fear memory
consolidation in the basolateral amygdala. FASEB J 26: 3649 –3657, 2012.
358. Salter MG, Fern R. NMDA receptors are expressed in developing oligodendrocyte
processes and mediate injury. Nature 438: 1167–1171, 2005.
361. Santello M, Bezzi P, Volterra A. TNFalpha controls glutamatergic gliotransmission in
the hippocampal dentate gyrus. Neuron 69: 988 –1001, 2011.
362. Santello M, Volterra A. TNFalpha in synaptic function: switching gears. Trends Neurosci 35: 638 – 647, 2012.
363. Sasaki T, Matsuki N, Ikegaya Y. Action-potential modulation during axonal conduction. Science 331: 599 – 601, 2011.
364. Schafer DP, Lehrman EK, Stevens B. The “quad-partite” synapse: microglia-synapse
interactions in the developing and mature CNS. Glia 61: 24 –36, 2013.
365. Schiffer T, Schulte S, Sperlich B, Achtzehn S, Fricke H, Struder HK. Lactate infusion at
rest increases BDNF blood concentration in humans. Neurosci Lett 488: 234 –237,
2011.
366. Schmalbruch IK, Linde R, Paulson OB, Madsen PL. Activation-induced resetting of
cerebral metabolism and flow is abolished by beta-adrenergic blockade with propranolol. Stroke 33: 251–255, 2002.
367. Scholz J, Klein MC, Behrens TE, Johansen-Berg H. Training induces changes in whitematter architecture. Nat Neurosci 12: 1370 –1371, 2009.
368. Schummers J, Yu H, Sur M. Tuned responses of astrocytes and their influence on
hemodynamic signals in the visual cortex. Science 320: 1638 –1643, 2008.
369. Schurr A, Payne RS, Miller JJ, Rigor BM. Brain lactate is an obligatory aerobic energy
substrate for functional recovery after hypoxia: further in vitro validation. J Neurochem
69: 423– 426, 1997.
370. Schurr A, Payne RS, Miller JJ, Tseng MT, Rigor BM. Blockade of lactate transport
exacerbates delayed neuronal damage in a rat model of cerebral ischemia. Brain Res
895: 268 –272, 2001.
371. Seifert S, Pannell M, Uckert W, Farber K, Kettenmann H. Transmitter- and hormoneactivated Ca2⫹ responses in adult microglia/brain macrophages in situ recorded after
viral transduction of a recombinant Ca2⫹ sensor. Cell Calcium 49: 365–375, 2011.
383. Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature 440:
1054 –1059, 2006.
384. Stenovec M, Kreft M, Grilc S, Potokar M, Kreft ME, Pangrsic T, Zorec R. Ca2⫹dependent mobility of vesicles capturing anti-VGLUT1 antibodies. Exp Cell Res 313:
3809 –3818, 2007.
385. Stevens B, Porta S, Haak LL, Gallo V, Fields RD. Adenosine: a neuron-glial transmitter
promoting myelination in the CNS in response to action potentials. Neuron 36: 855–
868, 2002.
386. Stigliani S, Zappettini S, Raiteri L, Passalacqua M, Melloni E, Venturi C, Tacchetti C,
Diaspro A, Usai C, Bonanno G. Glia re-sealed particles freshly prepared from adult rat
brain are competent for exocytotic release of glutamate. J Neurochem 96: 656 – 668,
2006.
387. Stout CE, Costantin JL, Naus CC, Charles AC. Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J Biol Chem 277: 10482–10488,
2002.
388. Suadicani SO, Brosnan CF, Scemes E. P2X7 receptors mediate ATP release and
amplification of astrocytic intercellular Ca2⫹ signaling. J Neurosci 26: 1378 –1385,
2006.
389. Suadicani SO, Iglesias R, Wang J, Dahl G, Spray DC, Scemes E. ATP signaling is
deficient in cultured Pannexin1-null mouse astrocytes. Glia 60: 1106 –1116, 2012.
390. Sun F, Dai C, Xie J, Hu X. Biochemical issues in estimation of cytosolic free NAD/
NADH ratio. PLoS One 7: e34525, 2012.
391. Sun H, Tsunenari T, Yau KW, Nathans J. The vitelliform macular dystrophy protein
defines a new family of chloride channels. Proc Natl Acad Sci USA 99: 4008 – 4013,
2002.
392. Sunkaria A, Bhardwaj S, Halder A, Yadav A, Sandhir R. Migration and phagocytic ability
of activated microglia during post-natal development is mediated by calcium-dependent purinergic signalling. Mol Neurobiol. In press.
373. Sherwood CC, Stimpson CD, Raghanti MA, Wildman DE, Uddin M, Grossman LI,
Goodman M, Redmond JC, Bonar CJ, Erwin JM, Hof PR. Evolution of increased
glia-neuron ratios in the human frontal cortex. Proc Natl Acad Sci USA 103: 13606 –
13611, 2006.
393. Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, Alberini CM.
Astrocyte-neuron lactate transport is required for long-term memory formation. Cell
144: 810 – 823, 2011.
374. Shigetomi E, Bowser DN, Sofroniew MV, Khakh BS. Two forms of astrocyte calcium
excitability have distinct effects on NMDA receptor-mediated slow inward currents in
pyramidal neurons. J Neurosci 28: 6659 – 6663, 2008.
394. Suzuki T, Hide I, Ido K, Kohsaka S, Inoue K, Nakata Y. Production and release of
neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia. J Neurosci 24: 1–7, 2004.
375. Shigetomi E, Jackson-Weaver O, Huckstepp RT, O’Dell TJ, Khakh BS. TRPA1 channels are regulators of astrocyte basal calcium levels and long-term potentiation via
constitutive D-serine release. J Neurosci 33: 10143–10153, 2013.
395. Takano T, Kang J, Jaiswal JK, Simon SM, Lin JH, Yu Y, Li Y, Yang J, Dienel G, Zielke HR,
Nedergaard M. Receptor-mediated glutamate release from volume sensitive channels
in astrocytes. Proc Natl Acad Sci USA 102: 16466 –16471, 2005.
724
Physiol Rev • VOL 95 • JULY 2015 • www.prv.org
NEUROGLIAL TRANSMISSION
396. Takata N, Mishima T, Hisatsune C, Nagai T, Ebisui E, Mikoshiba K, Hirase H. Astrocyte calcium signaling transforms cholinergic modulation to cortical plasticity in vivo. J
Neurosci 31: 18155–18165, 2011.
415. Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW,
Inoue K. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve
injury. Nature 424: 778 –783, 2003.
397. Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, Dziewczapolski
G, Nakamura T, Cao G, Pratt AE, Kang YJ, Tu S, Molokanova E, McKercher SR, Hires
SA, Sason H, Stouffer DG, Buczynski MW, Solomon JP, Michael S, Powers ET, Kelly
JW, Roberts A, Tong G, Fang-Newmeyer T, Parker J, Holland EA, Zhang D, Nakanishi
N, Chen HS, Wolosker H, Wang Y, Parsons LH, Ambasudhan R, Masliah E, Heinemann SF, Pina-Crespo JC, Lipton SA. A␤ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci USA 110:
E2518 –E2527, 2013.
416. Ueda M, Muramatsu H, Kamiya T, Muramatsu A, Mori T, Terashi A, Katayama Y.
Pyruvate dehydrogenase activity and energy metabolite levels following bilateral common carotid artery occlusion in rat brain. Life Sci 67: 821– 826, 2000.
398. Tang F, Lane S, Korsak A, Paton JF, Gourine AV, Kasparov S, Teschemacher AG.
Lactate-mediated glia-neuronal signalling in the mammalian brain. Nat Commun 5:
3284, 2014.
417. Ullian EM, Sapperstein SK, Christopherson KS, Barres BA. Control of synapse number
by glia. Science 291: 657– 661, 2001.
418. Vafaee MS, Vang K, Bergersen LH, Gjedde A. Oxygen consumption and blood flow
coupling in human motor cortex during intense finger tapping: implication for a role of
lactate. J Cereb Blood Flow Metab 32: 1859 –1868, 2012.
419. Van Hall G, Stromstad M, Rasmussen P, Jans O, Zaar M, Gam C, Quistorff B, Secher
NH, Nielsen HB. Blood lactate is an important energy source for the human brain. J
Cereb Blood Flow Metab 29: 1121–1129, 2009.
399. Taylor DL, Diemel LT, Cuzner ML, Pocock JM. Activation of group II metabotropic
glutamate receptors underlies microglial reactivity and neurotoxicity following stimulation with chromogranin A, a peptide up-regulated in Alzheimer’s disease. J Neurochem 82: 1179 –1191, 2002.
420. Van Praag H, Fleshner M, Schwartz MW, Mattson MP. Exercise, energy intake, glucose homeostasis, and the brain. J Neurosci 34: 15139 –15149, 2014.
400. Taylor DL, Diemel LT, Pocock JM. Activation of microglial group III metabotropic
glutamate receptors protects neurons against microglial neurotoxicity. J Neurosci 23:
2150 –2160, 2003.
421. Velez-Fort M, Maldonado PP, Butt AM, Audinat E, Angulo MC. Postnatal switch from
synaptic to extrasynaptic transmission between interneurons and NG2 cells. J Neurosci 30: 6921– 6929, 2010.
401. Taylor DL, Jones F, Kubota ES, Pocock JM. Stimulation of microglial metabotropic
glutamate receptor mGlu2 triggers tumor necrosis factor alpha-induced neurotoxicity in concert with microglial-derived Fas ligand. J Neurosci 25: 2952–2964,
2005.
422. Velez-Fort M, Maldonado PP, Butt AM, Audinat E, Angulo MC. Postnatal switch from
synaptic to extrasynaptic transmission between interneurons and NG2 cells. J Neurosci 30: 6921– 6929, 2010.
402. Tekkök SB, Goldberg MP. AMPA/kainate receptor activation mediates hypoxic oligodendrocyte death and axonal injury in cerebral white matter. J Neurosci 21: 4237–
4248, 2001.
403. Thomas AG, O’Driscoll CM, Bressler J, Kaufmann W, Rojas CJ, Slusher BS. Small
molecule glutaminase inhibitors block glutamate release from stimulated microglia.
Biochem Biophys Res Commun 443: 32–36, 2014.
423. Venero JL, Santiago M, Tomas-Camardiel M, Matarredona ER, Cano J, Machado A.
DCG-IV but not other group-II metabotropic receptor agonists induces microglial
BDNF mRNA expression in the rat striatum. Correlation with neuronal injury. Neuroscience 113: 857– 869, 2002.
424. Ventura R, Harris KM. Three-dimensional relationships between hippocampal synapses and astrocytes. J Neurosci 19: 6897– 6906, 1999.
404. Thomas C, Baker CI. Teaching an adult brain new tricks: a critical review of
evidence for training-dependent structural plasticity in humans. Neuroimage 73:
225–236, 2013.
425. Verderio C, Cagnoli C, Bergami M, Francolini M, Schenk U, Colombo A, Riganti L,
Frassoni C, Zuccaro E, Danglot L, Wilhelm C, Galli T, Canossa M, Matteoli M. TIVAMP/VAMP7 is the SNARE of secretory lysosomes contributing to ATP secretion
from astrocytes. Biol Cell 104: 213–228, 2012.
405. Thompson RJ, Jackson MF, Olah ME, Rungta RL, Hines DJ, Beazely MA, MacDonald
JF, MacVicar BA. Activation of pannexin-1 hemichannels augments aberrant bursting
in the hippocampus. Science 322: 1555–1559, 2008.
425a.Voloboueva LA, Emery JF, Sun X, Giffard RG. Inflammatory response of microglial
BV-2 cells includes a glycolytic shift and is modulated by mitochondrial glucose-regulated protein 75/mortalin. FEBS Lett 587: 756 –762, 2013.
406. Tong G, Jahr CE. Block of glutamate transporters potentiates postsynaptic excitation.
Neuron 13: 1195–1203, 1994.
426. Volterra A, Liaudet N, Savtchouk I. Astrocyte Ca2⫹ signalling: an unexpected complexity. Nat Rev Neurosci 15: 327–335, 2014.
407. Tong XP, Li XY, Zhou B, Shen W, Zhang ZJ, Xu TL, Duan S. Ca2⫹ signaling evoked by
activation of Na⫹ channels and Na⫹/Ca2⫹ exchangers is required for GABA-induced
NG2 cell migration. J Cell Biol 186: 113–128, 2009.
427. Von BG, Trotter J, Kettenmann H. Expression and developmental regulation of a
GABAA receptor in cultured murine cells of the oligodendrocyte lineage. Eur J Neurosci 3: 310 –316, 1991.
408. Torp R, Danbolt NC, Babaie E, Bjoras M, Seeberg E, Storm-Mathisen J, Ottersen OP.
Differential expression of two glial glutamate transporters in the rat brain: an in situ
hybridization study. Eur J Neurosci 6: 936 –942, 1994.
428. Wake H, Lee PR, Fields RD. Control of local protein synthesis and initial events in
myelination by action potentials. Science 333: 1647–1651, 2011.
409. Trangmar SJ, Chiesa ST, Stock CG, Kalsi KK, Secher NH, Gonzalez-Alonso J. Dehydration affects cerebral blood flow but not its metabolic rate for oxygen during
maximal exercise in trained humans. J Physiol 592: 3143–3160, 2014.
410. Traynelis SF, Cull-Candy SG. Pharmacological properties and H⫹ sensitivity of excitatory amino acid receptor channels in rat cerebellar granule neurones. J Physiol 433:
727–763, 1991.
411. Tremblay ME, Lowery RL, Majewska AK. Microglial interactions with synapses are
modulated by visual experience. PLoS Biol 8: e1000527, 2010.
412. Trkov S, Stenovec M, Kreft M, Potokar M, Parpura V, Davletov B, Zorec R. Fingolimod–a sphingosine-like molecule inhibits vesicle mobility and secretion in astrocytes.
Glia 60: 1406 –1416, 2012.
429. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. Resting microglia directly
monitor the functional state of synapses in vivo and determine the fate of ischemic
terminals. J Neurosci 29: 3974 –3980, 2009.
430. Walsh JG, Reinke SN, Mamik MK, McKenzie BA, Maingat F, Branton WG, Broadhurst
DI, Power C. Rapid inflammasome activation in microglia contributes to brain disease
in HIV/AIDS. Retrovirology 11: 35, 2014.
431. Walz W, Mukerji S. Lactate release from cultured astrocytes and neurons: a comparison. Glia 1: 366 –370, 1988.
432. Wang CM, Chang YY, Kuo JS, Sun SH. Activation of P2X(7) receptors induced
[3H]GABA release from the RBA-2 type-2 astrocyte cell line through a Cl⫺/HCO3⫺dependent mechanism. Glia 37: 8 –18, 2002.
413. Trotta T, Porro C, Calvello R, Panaro MA. Biological role of Toll-like receptor-4 in the
brain. J Neuroimmunol 268: 1–12, 2014.
433. Wang F, Smith NA, Xu Q, Goldman S, Peng W, Huang JH, Takano T, Nedergaard M.
Photolysis of caged Ca2⫹ but not receptor-mediated Ca2⫹ signaling triggers astrocytic glutamate release. J Neurosci 33: 17404 –17412, 2013.
414. Trotter J, Karram K, Nishiyama A. NG2 cells: properties, progeny and origin. Brain Res
Rev 63: 72– 82, 2010.
434. Wang M, Gamo NJ, Yang Y, Jin LE, Wang XJ, Laubach M, Mazer JA, Lee D, Arnsten AF.
Neuronal basis of age-related working memory decline. Nature 476: 210 –213, 2011.
Physiol Rev • VOL 95 • JULY 2015 • www.prv.org
725
GUNDERSEN ET AL.
435. Wang N, De BM, Decrock E, Bol M, Gadicherla A, Bultynck G, Leybaert L. Connexin
targeting peptides as inhibitors of voltage- and intracellular Ca2⫹-triggered Cx43
hemichannel opening. Neuropharmacology 75: 506 –516, 2013.
436. Wang X, Lou N, Xu Q, Tian GF, Peng WG, Han X, Kang J, Takano T, Nedergaard M.
Astrocytic Ca2⫹ signaling evoked by sensory stimulation in vivo. Nat Neurosci 9:
816 – 823, 2006.
437. Wang ZZ, Zhang Y, Liu YQ, Zhao N, Zhang YZ, Yuan L, An L, Li J, Wang XY, Qin JJ,
Wilson SP, O’Donnell JM, Zhang HT, Li YF. RNA interference-mediated phosphodiesterase 4D splice variants knock-down in the prefrontal cortex produces antidepressant-like and cognition-enhancing effects. Br J Pharmacol 168: 1001–1014, 2013.
438. Wemmie JA. Neurobiology of panic and pH chemosensation in the brain. Dialogues
Clin Neurosci 13: 475– 483, 2011.
439. Wen Q, Chklovskii DB. Segregation of the brain into gray and white matter: a design
minimizing conduction delays. PLoS Comput Biol 1: 617– 630, 2005.
440. White R, Kramer-Albers EM. Axon-glia interaction and membrane traffic in myelin
formation. Front Cell Neurosci 7: 284, 2014.
441. Winter B, Breitenstein C, Mooren FC, Voelker K, Fobker M, Lechtermann A, Krueger
K, Fromme A, Korsukewitz C, Floel A, Knecht S. High impact running improves
learning. Neurobiol Learn Mem 87: 597– 609, 2007.
442. Witting A, Walter L, Wacker J, Moller T, Stella N. P2X7 receptors control 2-arachidonoylglycerol production by microglial cells. Proc Natl Acad Sci USA 101: 3214 –3219,
2004.
443. Wong AW, Xiao J, Kemper D, Kilpatrick TJ, Murray SS. Oligodendroglial expression of
TrkB independently regulates myelination and progenitor cell proliferation. J Neurosci
33: 4947– 4957, 2013.
444. Woo DH, Han KS, Shim JW, Yoon BE, Kim E, Bae JY, Oh SJ, Hwang EM, Marmorstein
AD, Bae YC, Park JY, Lee CJ. TREK-1 and Best1 channels mediate fast and slow
glutamate release in astrocytes upon GPCR activation. Cell 151: 25– 40, 2012.
445. Xu J, Peng H, Kang N, Zhao Z, Lin JH, Stanton PK, Kang J. Glutamate-induced
exocytosis of glutamate from astrocytes. J Biol Chem 282: 24185–24197, 2007.
446. Yaguchi T, Nishizaki T. Extracellular high K⫹ stimulates vesicular glutamate release
from astrocytes by activating voltage-dependent calcium channels. J Cell Physiol 225:
512–518, 2010.
447. Yang J, Ruchti E, Petit JM, Jourdain P, Grenningloh G, Allaman I, Magistretti PJ. Lactate
promotes plasticity gene expression by potentiating NMDA signaling in neurons. Proc
Natl Acad Sci USA 111: 12228 –12233, 2014.
726
448. Yang QK, Xiong JX, Yao ZX. Neuron-NG2 cell synapses: novel functions for regulating NG2 cell proliferation and differentiation. Biomed Res Int 2013: 402843, 2013.
449. Yang Y, Ge W, Chen Y, Zhang Z, Shen W, Wu C, Poo M, Duan S. Contribution of
astrocytes to hippocampal long-term potentiation through release of D-serine. Proc
Natl Acad Sci USA 100: 15194 –15199, 2003.
450. Ye ZC, Oberheim N, Kettenmann H, Ransom BR. Pharmacological “cross-inhibition”
of connexin hemichannels and swelling activated anion channels. Glia 57: 258 –269,
2009.
451. Ye ZC, Wyeth MS, Baltan-Tekkok S, Ransom BR. Functional hemichannels in astrocytes: a novel mechanism of glutamate release. J Neurosci 23: 3588 –3596, 2003.
452. Yoon BE, Jo S, Woo J, Lee JH, Kim T, Kim D, Lee CJ. The amount of astrocytic GABA
positively correlates with the degree of tonic inhibition in hippocampal CA1 and
cerebellum. Mol Brain 4: 42, 2011.
453. Yoon JJ, Green CR, O’Carroll SJ, Nicholson LF. Dose-dependent protective effect of
connexin43 mimetic peptide against neurodegeneration in an ex vivo model of epileptiform lesion. Epilepsy Res 92: 153–162, 2010.
454. Yu Y, Ugawa S, Ueda T, Ishida Y, Inoue K, Kyaw NA, Umemura A, Mase M, Yamada
K, Shimada S. Cellular localization of P2X7 receptor mRNA in the rat brain. Brain Res
1194: 45–55, 2008.
455. Yuan X, Eisen AM, McBain CJ, Gallo V. A role for glutamate and its receptors in the
regulation of oligodendrocyte development in cerebellar tissue slices. Development
125: 2901–2914, 1998.
456. Zatorre RJ, Fields RD, Johansen-Berg H. Plasticity in gray and white: neuroimaging
changes in brain structure during learning. Nat Neurosci 15: 528 –536, 2012.
457. Zhang Q, Fukuda M, Van BE, Pascual O, Haydon PG. Synaptotagmin IV regulates glial
glutamate release. Proc Natl Acad Sci USA 101: 9441–9446, 2004.
458. Zhang Q, Pangrsic T, Kreft M, Krzan M, Li N, Sul JY, Halassa M, Van BE, Zorec R,
Haydon PG. Fusion-related release of glutamate from astrocytes. J Biol Chem 279:
12724 –12733, 2004.
460. Zhang Y, Zhang H, Feustel PJ, Kimelberg HK. DCPIB, a specific inhibitor of volume
regulated anion channels (VRACs), reduces infarct size in MCAo and the release of
glutamate in the ischemic cortical penumbra. Exp Neurol 210: 514 –520, 2008.
461. Zhang Z, Chen G, Zhou W, Song A, Xu T, Luo Q, Wang W, Gu XS, Duan S. Regulated
ATP release from astrocytes through lysosome exocytosis. Nat Cell Biol 9: 945–953,
2007.
462. Ziskin JL, Nishiyama A, Rubio M, Fukaya M, Bergles DE. Vesicular release of glutamate
from unmyelinated axons in white matter. Nat Neurosci 10: 321–330, 2007.
Physiol Rev • VOL 95 • JULY 2015 • www.prv.org