Physiol Rev 88: 983–1008, 2008;
doi:10.1152/physrev.00036.2007.
Activity-Dependent Structural and Functional Plasticity
of Astrocyte-Neuron Interactions
DIONYSIA T. THEODOSIS, DOMINIQUE A. POULAIN, AND STÉPHANE H. R. OLIET
Neurocenter Magendie, Institut National de la Santé et de la Recherche Médicale U. 862 and University Victor
Segalen-Bordeaux 2, Bordeaux, France
I. Introduction
II. Astrocyte-Neuron Interactions During Basal Neuronal Activity
A. Distal astrocytic processes ensheath neurons and their synapses
B. Astrocytes and the extracellular space
C. Neuron to astrocyte signaling
D. Gliotransmission
III. Astrocyte-Neuron Interactions Are Modified by Neuronal Activity
A. Mobility of astrocytic processes
B. Consequences on extracellular homeostasis
C. Consequences on excitatory and inhibitory neurotransmission
D. Effects on gliotransmission
E. Astrocytic changes and synaptic remodeling
IV. Physiological Consequences of Astrocyte-Neuron Plasticity
A. Neuroendocrine regulations
B. Learning and memory
V. Astrocyte-Neuron Interactions and Neuropathological Conditions
VI. Cellular Mechanisms Underlying Astrocyte-Neuron Plasticity
A. Permissive molecular factors
B. Signaling molecules
C. Cytoskeletal changes
VII. Conclusions and Perspectives
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Theodosis DT, Poulain DA, Oliet SHR. Activity-Dependent Structural and Functional Plasticity of AstrocyteNeuron Interactions. Physiol Rev 88: 983–1008, 2008; doi:10.1152/physrev.00036.2007.—Observations from different
brain areas have established that the adult nervous system can undergo significant experience-related structural
changes throughout life. Less familiar is the notion that morphological plasticity affects not only neurons but glial
cells as well. Yet there is abundant evidence showing that astrocytes, the most numerous cells in the mammalian
brain, are highly mobile. Under physiological conditions as different as reproduction, sensory stimulation, and
learning, they display a remarkable structural plasticity, particularly conspicuous at the level of their lamellate distal
processes that normally ensheath all portions of neurons. Distal astrocytic processes can undergo morphological
changes in a matter of minutes, a remodeling that modifies the geometry and diffusion properties of the extracellular
space and relationships with adjacent neuronal elements, especially synapses. Astrocytes respond to neuronal
activity via ion channels, neurotransmitter receptors, and transporters on their processes; they transmit information
via release of neuroactive substances. Where astrocytic processes are mobile then, astrocytic-neuronal interactions
become highly dynamic, a plasticity that has important functional consequences since it modifies extracellular ionic
homeostasis, neurotransmission, gliotransmission, and ultimately neuronal function at the cellular and system
levels. Although a complete picture of intervening cellular mechanisms is lacking, some have been identified, notably
certain permissive molecular factors common to systems capable of remodeling (cell surface and extracellular
matrix adhesion molecules, cytoskeletal proteins) and molecules that appear specific to each system (neuropeptides, neurotransmitters, steroids, growth factors) that trigger or reverse the morphological changes.
I. INTRODUCTION
Neurons and glia are not independent cellular elements of the nervous system but two strongly interconwww.prv.org
nected components. Intensive research in the past decade
has revealed new, important roles for the latter. Probably
the least expected finding has been that information processing is not an exclusive property of neurons but that it
0031-9333/08 $18.00 Copyright © 2008 the American Physiological Society
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is shared by astrocytes, the most abundant glial cells in
the central nervous system (CNS). Astrocytes thus participate in a number of interactions that are central to the
development, function, and repair of the CNS. The wealth
of new observations have resulted in a decided movement
away from the prevalent neuron-centric vision of nervous
system function. Without assuming an entirely gliocentric
vision, it is obvious that astrocytes, in addition to their
more ancillary functions of structural and nutritional support, intervene in the regulation of synaptic function and
are active partners in information processing, a topic
much reviewed recently (see, for example, Refs. 76, 125,
200).
Work over the past 25 years has rendered yet another
dogma about the adult CNS obsolete. Ramon y Cajal (154)
had concluded that its structure remains essentially stable
once it reaches full development, changing only in response to increasing age and degeneration. Numerous
observations have shown that this is not the case. Thus
careful electron microscopic analyses of different neuronal systems described a surprising capacity of neurons
and their synaptic connections to undergo significant
morphological alterations. Today, direct fluorescent imaging approaches, especially on live tissues, confirm and
extend many of these earlier findings. We can no longer
ignore, therefore, that neurons can change their form
throughout life, during a variety of physiological conditions that modify neuronal activity. Much attention has
been given to the incredible turnover of dendritic spines,
and presumably of excitatory synapses, under different
conditions (reviewed in Ref. 2). However, it is not necessary to limit oneself to dendritic spine remodeling to
illustrate the brain’s remarkable capacity for structural
change. Examples of axonal and synaptic transformations
under different physiological conditions are abundant (8,
32, 57, 184, 201). The shape and size of somata can change
as well (8, 184), while large-scale structural changes in
major dendritic branches have been documented in many
systems (153, 168, 199).
The same methodologies have revealed that it is not
only neurons that can undergo remodeling but glial cells
as well. In particular, it is clear that astrocytes, a major
class of glia in the vertebrate CNS, are remarkably dynamic. Structural changes can be detected not only at the
level of their somata and large processes but most importantly for neuronal function, at the level of their fine,
lamellate distal processes that ensheath neuronal elements, including synapses. This review focuses on this
latter form of astrocytic-neuronal plasticity. We shall
show that it is experience-dependent, occurring during
conditions as different as reproductive status, enriched
sensory input, learning, and memory. We then describe
how such morphological changes modify neuronal function. Finally, we discuss molecular and cellular mechanisms that may help us to understand how this kind of
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plasticity occurs in an organ that we thought overly endowed with enough cells and circuits to ensure its complex activities.
II. ASTROCYTE-NEURON INTERACTIONS
DURING BASAL NEURONAL ACTIVITY
A. Distal Astrocytic Processes Ensheath Neurons
and Their Synapses
Astrocytes are numerous in the vertebrate CNS, and
their number is enhanced considerably with phylogeny
and increasing brain complexity. For example, in the
nervous system of lower species like Caenorhabditis
elegans, neurons outnumber glia by 6:1, while in the
mouse or rat cortex, the ratio of astrocytes to neurons is
1:3. In the human cortex, there are 1.4 astrocytes per
neuron (125). They were the original neuroglia visualized
by Ramon y Cajal, after examination of neocortical sections treated with a gold sublimate stain (154) (Fig. 1A).
The stain targeted intermediate filaments, the most prominent cytological feature of these cells, that we know now
consist mainly of glial fibrillary acidic protein (GFAP).
Recent work from various sources has confirmed and
extended Ramon y Cajal’s observations.
The most common astrocytes in the gray matter,
called stellate or protoplasmic (in contrast to fibrous
astrocytes in white matter), have an intricate, complex
morphology, consisting of a relatively small cell body with
several thick processes extending into the neuronal network from which arise numerous fine processes (Fig. 1,
A–D). The latter are generally 30 – 40 ␮m in length and
appear as thin, veil-like lamellae within the neuropile
(Figs. 1 and 2). Ramon y Cajal (154) had noted the complexity of these processes and appreciated their close
relationship to neuronal and vascular elements (Fig. 1A).
As seen with electron microscopy, these leafletlike processes ensheath all neuronal somata, dendrites, and synapses (Fig. 2, A and C). However, the extent of this
ensheathment varies in different systems, indicating that
there are specializations of astrocytic-neuronal interactions at the local level, even under normal conditions. For
example, in the neocortex, astrocytic processes only partially cover pre- and postsynaptic elements of axodendritic glutamatergic synapses (195), while in the cerebellar cortex, Bergmann glia processes almost totally encapsulate synapses between parallel fibers and Purkinje cell
spines (65). In the rat visual cortex, layer I synapses have
the least and layers II/III the most extensive astrocytic
coverage (90).
The structural complexity of astrocytes also increases with phylogeny so that the human cortex contains
the largest and most elaborate astrocytes (134) (Fig. 1, C
and D). In addition, a given population of astrocytes in
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FIG. 1. Astrocytes display a complex morphology. A: using basic histological approaches, Cajal saw that protoplasmic astrocytes (dark cells)
possess a relatively small soma and several thick processes whose fine distal extremities ensheath neighboring neuronal somata and dendrites.
[Courtesy of the Cajal Institute (CSIC), Madrid, Spain.] B and C: live in situ labeling techniques using green fluorescent protein (GFP), illustrated
here in the supraoptic nucleus (SON) of the hypothalamus (B) and in the cortex (C), reveal the remarkable complexity of distal astrocytic processes.
[Courtesy of J. Tasker (B) and M. Nedergaard (C).] D: intracellular labeling of two neighboring astrocytes in the hippocampus with different
fluorescent markers [biocytin-conjugated cascade blue (red) and Lucifer yellow, green] shows little overlap of distal branches. [Modified from Ogata
and Kosaka (135).] E: in contrast, GFAP immunolabeling only renders astrocytic somata and thick processes visible. The example shows reactive
astrocytes in the cortex after a mechanical lesion.
any one brain region can be quite heterogeneous (48). In
the supraoptic nucleus (SON) of the rodent hypothalamus
in which they have been extensively analyzed, there are at
least two types, with distinct morphologies and electrophysiological properties (17, 87). In this nucleus, in addition to classic protoplasmic astrocytes (Figs. 1B and 2A),
there is a radial type that resembles interlaminal astrocytes in the adult primate cortex and polarized human
cortical astrocytes (134).
While GFAP immunolabeling is still generally considered a reliable means to identify astrocytes, it should be
interpreted with caution since it does not do full justice to
the complex morphology of the cells. Indeed, under normal conditions, astrocytes may express no GFAP or so
little that it remains undetectable with immunocytochemistry. When GFAP immunoreactivity is rendered visible, it
is found in cell bodies and thick processes. This is illustrated clearly by reactive astrocytes that appear in many
neuropathologies and for reasons that we still ignore,
express high levels of GFAP (Fig. 1E), together with
vimentin, another intermediate filament protein (157). In
contrast, distal astrocytic processes contain little cytoplasm and lack most intracellular organelles, including
intermediate filaments and therefore GFAP. Their simple
morphology is illustrated well with electron microscopy
(Fig. 2, A and C) (65, 103, 185), immunocytochemical
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labeling for intracellular proteins (Fig. 2, B–E) (39, 135),
or live imaging of cells filled completely with different
fluorescent markers (Fig. 1, B–D) (13, 24, 125). Because of
the profusion of these distal processes, we should consider the overall morphology of astrocytes as polyhedral,
rather than starlike.
Ramon y Cajal (154) had noted that there was very
little overlap between the distal processes of two adjacent
cells and suggested that individual glial cells delineate
distinct domains within the neuropile. Indeed, intracellular filling of cells with different fluorescent markers, in the
hippocampus (134) and cortex (135) for example, revealed that astrocytes occupy highly segregated domains,
an anatomical configuration that is not evident when the
cells are labeled for GFAP (Fig. 1E). Moreover, this kind
of cell labeling established that astrocytic processes
rarely extend beyond a 50-␮m radius and that there is only
limited overlap in the peripheral portions of neighboring
cells (Fig. 1D) (69, 134, 135). A recent study (69) estimated that a single astrocyte enwraps 4 – 8 neuronal somata and 300 – 600 dendrites and creates a kind of synaptic island defined by its ensheathing processes. It is obvious, then, that the classical image of an astrocytic
syncytium in a large area of nervous tissue has to be
replaced by one of more restrained, independent glial
microdomains. Functionally, this is of primary impor-
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FIG. 2. The fine distal processes of astrocytes ensheath neuronal elements. A: electron microscopy clearly shows the lamella-like nature of these
processes (in blue) which are normally intercalated between neighboring neuronal somata and dendrites and which surround synapses (syn). Note
that these processes are so thin they lack most intracellular organelles. The example is from the rat SON under basal conditions of neurosecretion.
[Adapted from Montagnese et al. (118).] B and C: astrocytic processes are enriched in transporters, like GLT-1, that clear away synaptically released
glutamate transporters. Immunocytochemical labeling shows GLT-1 immunoreactivity in the neuropile around immunonegative neuronal profiles in
the rat SON, visualized with epifluorescence (B) and with electron microscopy after immunoperoxidase labeling (C). As illustrated in C, GLT-1
immunoreactivity is clearly associated with lamellate astrocytic processes surrounding pre- (syn.) and postsynaptic (dend.) elements. D and
E: astrocytic processes contain gliotransmitters, like D-serine. After single immunolabeling of the SON, D-serine immunofluorescence is visible in the
neuropile around immunonegative neuronal somata and in the cytoplasm of astrocytic somata (arrows and at higher magnification in the inset).
After double immunolabeling, D-serine immunoreactivity (green) is not detected in neuronal elements, identified here as oxytocinergic (OT) profiles
(red) or putative vasopressinergic (black). [Modified from Panatier et al. (141).]
tance, since it means that astrocytes are capable of interacting with neurons in a restricted microenvironment.
B. Astrocytes and the Extracellular Space
The fine distal processes of astrocytes are interposed
between all neuronal elements (Figs. 1A and 2; see also
Fig. 8). By their mere presence, then, they can be considered a physical barrier to restrict spillover and diffusion
of locally released, potentially active molecules into the
extracellular space (ECS). Moreover, by their position,
they contribute to the regulation of the microenvironment
in which neurons develop and function, maintaining a
tight control on local ion and pH homeostasis, delivering
glucose, providing metabolic substrates, and clearing
away metabolic waste. For example, the concentration of
extracellular K⫹ needs to be tightly regulated since its
accumulation in the ECS can alter neuronal excitability
dramatically. Astrocytes take up this ion via the glial
isoform of the Na⫹/K⫹ pump or through specific ion
channels, like inward-rectifying K⫹ channels (79, 129).
They then transfer it from sites of accumulation to areas
with lower concentrations, to finally extrude it in the ECS
and/or into the circulation, a kind of K⫹ spatial buffering
that may depend on gap junction coupling (197). Another
example is the regulation of extracellular levels of Na⫹,
particularly important in sensory circumventricular orPhysiol Rev • VOL
gans like the subfornical organ and the organum vasculosum of the lamina terminalis, brain loci involved in the
control of salt/water intake (164, 204). These structures
contain brain Na⫹ sensors, the Na⫹x sodium channels
that accumulate on perineuronal astrocytic processes.
In these areas, then, astrocytes play an important role in
sensing the level of Na⫹ (164). As will be discussed in
detail in the next section, astrocytes, by expressing different transporters (Fig. 2, B and C), are also involved in
the clearance of synaptically released neurotransmitters,
like glutamate and GABA. Taken together, such passive
and active properties of astrocytes serve to limit interneuronal communication mediated by volume transmission
and prevent spillover of transmitters originating in synapses, thus preserving point-to-point neuronal communication (171).
In neurohemal structures like the neurohypophysis
and external layer of the median eminence, processes of
astrocytic-like cells (pituicytes and tanycytes, respectively) enclose neurosecretory axons (193). They thus
limit potential paracrine and/or autocrine actions of secreted peptides. In addition, these glial processes abut on
perivascular spaces, thereby physically restricting access
of neurosecretory terminals to the perivascular basal lamina (73, 176) (Fig. 3). Acting as a kind of physical barrier,
then, astrocytic processes affect neurosecretion, since
their presence limits diffusion of neurohormones released
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confined to the immature CNS, where they contribute to
the dynamic cell interactions characterizing its development, that of molecules like PSA-NCAM and the tenascins
persists in adult neuronal systems endowed with the capacity for plasticity (15, 89, 98, 180). Notable examples are
the hypothalamoneurohypophysial system (HNS) (Fig. 4),
the hippocampus, and the olfactory bulb.
C. Neuron to Astrocyte Signaling
FIG. 3. Astrocytic processes in neurohemal structures. As seen with
electron microscopy, in the neurohypophysis under basal conditions of
neurosecretion, fine processes of astrocytic-like cells, the pituicytes
(pit.) ensheath neurosecretory axons and terminals (ter.) and contact
⬃60% of the perivascular area (arrows); ⬃40% is covered by neurosecretory terminals. This proportion is reversed after stimulation of neurosecretion which results in a retraction of pituicyte processes from the
basal lamina. [Adapted from Theodosis and MacVicar (176) and Theodosis and Poulain (184).]
into perivascular spaces and ultimately into the general
circulation.
The plasmalemma of astrocytes, and in particular, of
their distal processes, is enriched with glycoproteins that
contribute to the molecular composition and complexity
of the ECS. An example is the highly sialylated isoform of
the neural cell adhesion molecule (PSA-NCAM) (Fig. 4C),
member of the immunoglobulin superfamily of cell adhesion molecules. Polysialic acid (PSA) is a long, linear
homopolymer of ␣-2-8-linked sialic acid attached to the
extracellular domain of NCAM, a complex sugar whose
large hydrated volume and polyanionic structure reduces
adhesion between cells and the ECS. PSA can also affect
the expression of receptors and transporters, and ultimately, neuronal and glial function (reviewed in Refs. 15,
98). In addition, astrocytes secrete into the ECS large,
complex glycoproteins like tenascins and chondroitin sulfate proteoglycans (100). The latter molecules are important not only as structural elements of the ECS but as
active partners in cell-to-cell communication via interactions with other cell surface glycoproteins, ionotropic/
metabotropic receptors, ion channels, trophic factor receptors, and small GTPases of the RAS family (43). While
the expression of most of these glycoproteins is generally
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Astrocytes can sense neuronal activity through a rich
panoply of neurotransmitter receptors and ion channels
that accumulate in their fine processes (see Refs. 7, 196).
This is of fundamental importance and has been conserved evolutionarily in both invertebrate and vertebrate
glia. Astrocytes respond to synaptically released neurotransmitters and other signaling substances with transient
elevations of cytosolic Ca2⫹ (196). These Ca2⫹ transients,
resulting from release of Ca2⫹ from internal stores, are
induced by activation of metabotropic receptors. Initially
described in astrocytes in culture, they have now been
detected in vivo. For example, robust increases in cytosolic Ca2⫹ were recorded in the barrel cortex in response
to repetitive whisker stimulation (203) and in the somatosensory cortex after sensory stimulation from the hindlimb (207). The responses appeared restricted to individual astrocytes. Increased extracellular levels of K⫹ can
also induce Ca2⫹ transients in astrocytes (71). Such signaling may alter gene expression and initiate morphological changes. It is at the basis of the astrocytic contribution to the maintenance of local microvascular tone as
well (76). On the other hand, there has been a developing
consensus that these Ca2⫹ elevations induce astrocytes
themselves to release glutamate, which then activates
adjacent neurons via pre- and postsynaptic receptor activation (reviewed in Refs. 76, 200). Nevertheless, the validity of the latter mechanism to explain rapid astrocyteneuron interactions has been questioned, since Ca2⫹ elevations in hippocampal astrocytes did not induce any
significant rises in cytosolic Ca2⫹ in adjacent pyramidal
neurons nor did they affect their electrical activity (50).
Cytosolic Ca2⫹ elevations can develop into Ca2⫹ oscillations, or repetitive increases of Ca2⫹ within single
cells (see Ref. 134). Modulation of the Ca2⫹ signal occurs
at discrete regions of distal processes and controls intracellular propagation of the signal (143). Since one astrocyte covers many synapses (69), this would be a means to
ensure that not all are affected in the same way by Ca2⫹
propagation. Cytosolic Ca2⫹ elevations may also be transformed into Ca2⫹ waves that propagate radially from one
single cell to neighboring cells, thus transferring the glial
signal at a distance from its site of origin. The principal
mechanism of wave propagation appears to be release of
ATP from one cell which then acts as a diffusible extra-
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THEODOSIS, POULAIN, AND OLIET
FIG. 4. Adult astrocytes that can undergo remodeling express cell adhesion
molecules permissive for structural plasticity. Light (A and B) and electron (C and D)
microscopy show that a hypothalamic center like the SON is enriched in immunoreactivity for the highly sialylated isoform of
NCAM (PSA-NCAM), known for its importance in cell-cell and cell-matrix interactions in the developing and adult nervous
systems. Note the restricted expression of
this molecule in the SON and its absence in
the adjacent hypothalamus (A). PSA-NCAM
immunoreactivity is strongly expressed in
the astrocytes of this structure, and particularly, in the fine astrocytic-like processes
that surround immunonegative neuronal
somata, dendrites (d), and synapses (sy)
(B–D). [A and B modified from Theodosis
et al. (186); C and D modified from Theodosis et al. (173).]
cellular messenger to activate neighboring cells (reviewed in Refs. 76, 125). Another mechanism is direct
communication through gap junctions, clearly seen in
cultured astrocytes from the striatum (61, 82) and cortex
(196). While intercellular propagation of Ca2⫹ waves may
explain communication between distant cells (31), the
validity of this mechanism as a normal means of intercellular signaling is uncertain. It has been observed only
after intense electrical stimulation, and the phenomenon
shares many properties with spreading depression. In any
case, both modalities of astrocytic signaling can affect
surrounding neurons, which respond by prolonged increases in cytosolic Ca2⫹ (see Ref. 125).
Distal astrocytic processes are also enriched in transporters that assure rapid and efficient removal of synapPhysiol Rev • VOL
tically released neurotransmitters, in particular glutamate
(Fig. 2, B and C). At very high concentrations, this excitatory amino acid can be highly toxic to neurons. Under
normal circumstances, astrocytes quickly remove glutamate at synaptic sites and thus contribute actively to the
regulation of synaptic transmission, a phenomenon that
has led us to change dramatically our thinking about
neurotransmission. Today we speak of the “tripartite”
synapse in which information flows not only between the
traditional pre- and postsynaptic neuronal partners but, in
addition, between these elements and adjacent astrocytic
processes (Fig. 5). This topic has gained ever-increasing
attention and is the subject of several reviews (for example, Ref. 7). For our purposes, we need to keep in mind
that if glutamate is not removed by astrocytic processes,
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(7, 94), which then activates glutamate receptors located
pre- or postsynaptically (Fig. 5). Thus activation of
postsynaptic NMDA receptors produces a slow transient
current that may contribute to network synchronization
(5, 49) while activation of presynaptic NMDA receptors
facilitates subsequent glutamate release, thereby favoring
neurotransmission (92). On the other hand, interaction
with metabotropic presynaptic receptors will inhibit neurotransmitter release (138).
There is increasing evidence that glutamate release
from astrocytes occurs via regulated exocytosis (6, 92,
142). The cells express protein components of the vesicular secretory apparatus, and gliotransmitter-mediated
actions are compromised when the exocytotic machinery
is impaired with specific neurotoxins. Vesicles that could
contain the amino acid prior to regulated exocytosis have
been visualized in these cells, including within distal processes next to synapses (119). Nevertheless, other mechanisms of release are possible, such as diffusion through
ionotropic purinergic receptors or unpaired connexons
(hemichannels) on the cell surface, through volume-activated chloride channels opened in response to swelling,
reversal of uptake by glutamate transporters, or via exchange of the amino acid by the cystine-glutamate antiporter (reviewed in Ref. 123). In any case, while a vesicular release mechanism may be of primary importance,
one or other of these latter mechanisms can exist in
parallel, especially under pathological conditions (see
Ref. 125).
FIG. 5. Distal astrocytic processes contribute to transmission at the
tripartite synapse. Synaptically released glutamate (gray arrows) stimulates ionotropic and metabotropic receptors on astrocytes. This then
activates intracellular pathways (black arrows) leading to release of
gliotransmitters (red arrows) that in turn act on pre- and postsynaptic
receptors. (Courtesy of A. Panatier.)
it will diffuse in the ECS. It can then interact with presynaptic metabotropic glutamate receptors on those very
excitatory synapses from which it was released, thus
inducing a feedback inhibition of its own release (138). In
addition, the amino acid can diffuse to neighboring synapses and, via similar presynaptic mechanisms, influence
the activity of other synapses, thereby contributing to
intersynaptic cross-talk (139, 148) (see Fig. 8).
D. Gliotransmission
Astrocytes themselves release several neuroactive
molecules, including glutamate, D-serine, ATP, taurine,
and cytokines like tumor necrosis factor (TNF)-␣.
1. Glutamate
As noted above, a rise in cytosolic Ca2⫹ is necessary
and sufficient to induce glutamate release from astrocytes
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2.
D-Serine
In some brain areas, astrocytes synthesize and release the amino acid D-serine (121, 141), considered an
important intermediary in glutamate neurotransmission
since it binds to the strychnine-insensitive glycine site and
serves as an endogenous coagonist of NMDA receptors
(see Fig. 9). Thus, in the hypothalamus (Fig. 2, D and E)
(141), hippocampus (165, 211), and retina (169), NMDA
receptor activity requires D-serine rather than glycine,
usually considered the coagonist of these receptors.
Through their release of D-serine, therefore, astrocytes
have become key elements in all physiological and pathological processes implicating NMDA receptors, from synaptic plasticity (211) to excitotoxicity (165). Like glutamate, there is growing evidence that this amino acid
accumulates in vesicles (M. Martineau, J. Puyal, R. Jahn,
D. Theodosis, and J. Mothet, unpublished observations),
presumably to be released by regulated exocytosis (121).
3. ATP and adenosine
Neurons have been considered the sole source of the
neuromodulators ATP and adenosine in the CNS, but
increasing evidence demonstrates that they derive from
astrocytes as well. Astrocytic ATP is presently considered
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THEODOSIS, POULAIN, AND OLIET
a major contributor to neuron-glia interactions, a topic
treated in depth in several recent reviews (51, 76, 132).
Released essentially via stimulus-dependent, vesicular
exocytosis (30, 152, 213), ATP acts on P2Y receptors in
astrocytes in which it triggers intracellular Ca2⫹ release
and Ca2⫹ wave propagation (67, 128). Moreover, such
signaling is coupled to Ca2⫹-dependent exocytosis of glutamate (51). Additionally, ATP can signal neighboring
neurons via interactions with pre- or postsynaptic purinergic receptors. In the hippocampus, excitation of presynaptic P2Y receptors leads to a tonic downregulation of
glutamatergic synaptic transmission (2, 12). In the hypothalamus, excitation of postsynaptic P2X receptors leads
to insertion of AMPA receptors in magnocellular neurons
(64), ultimately facilitating release of neuropeptides like
oxytocin (OT) and vasopressin (VP) (95).
Alternatively, ATP released from astrocytes may be
converted to adenosine by ectonucleotidases in the ECS.
Even a 1% conversion of ATP can result in an ⬃100-fold
increase in the extracellular concentration of adenosine
(44). Adenosine can induce a suppression of synaptic
transmission by activating adenosine A1 and/or A2 receptors that are positively or negatively coupled to K⫹ and
2⫹
Ca channels, respectively (127).
4. Taurine
Taurine is a gliotransmitter that acts as an endogenous ligand on strychnine-sensitive glycine receptors and
contributes to the osmoregulatory response. In the hypothalamic SON, for example, hyposmotic challenges lead
to the opening of volume-sensitive anion channels and
induction of taurine release from astrocytes. Taurine consequently binds to glycine receptors on magnocellular
neurons and induces membrane hyperpolarization (37,
81). How taurine is stored in astrocytes and how it is
released remain to be determined.
5. TNF-␣
Astrocytes can release different cytokines (161) and
express a variety of cytokine and chemokine receptors
(25) that intervene in the control of their proliferation,
growth, metabolism, and pathological reactions. Recent
studies have revealed that the proinflammatory cytokine
TNF-␣ can act as a gliotransmitter by promoting the neuronal insertion of AMPA receptors, an effect that requires
binding to TNF-1 receptors and activation of phosphatidylinositol (PI) 3-kinase (11, 167). Interestingly, removal
of TNF-␣ from brain slices reduced synaptic strength,
implying that this gliotransmitter is important both in
enhancing and maintaining synaptic strength. Its intracellular storage and mode of release are at present unknown.
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III. ASTROCYTE-NEURON INTERACTIONS ARE
MODIFIED BY NEURONAL ACTIVITY
A. Mobility of Astrocytic Processes
The relationship of astrocytes to their neighboring neurons is not a stable one, and there is presently ample evidence demonstrating that astrocytes constantly change
their morphology. First, GFAP immunolabeling shows
gross modifications in certain systems, even under normal
conditions, changes that are similar to those characterizing activated astrocytes under neuropathological conditions (157). They result in significantly altered expression
of GFAP together with remodeling of somata and thick
processes. They have been noted in hypothalamic areas
like the SON (14), suprachiasmatic nucleus (SCN) (12, 60,
108, 109), arcuate (55), and preoptic (59, 88) nuclei in
response to dehydration, circadian rhythmicity, and fluctuating sexual steroid levels, respectively. Such transformations also occur in the CA1 region of the hippocampus
(101) and visual cortex (91), during conditions of enriched sensory input. In the visual cortex, for example,
within 4 days exposure to an enriched environment,
concomitant to dendritic growth, there is a significant
increase in the surface density of GFAP immunopositive processes (91).
Whether gross changes in astrocytic morphology like
those detected with GFAP immunolabeling are of consequence to neuronal activity is presently unknown. What is
more certain is that the distal, lamellate processes of
astrocytes, devoid of GFAP, are remarkably mobile, and
this glial restructuring does have important direct effects
on neuronal function. As will be discussed in detail below,
accumulating evidence makes it clear that remodeling of
distal astrocytic processes is closely linked to neuronal
activity and often occurs in concert with morphological
changes in neighboring neurons and synaptic inputs, a
kind of astrocytic-neuronal plasticity that highlights the
brain’s remarkable capacity for activity-dependent restructuring. In the hypothalamus, such remodeling results
in reduced astrocytic coverage of neuronal elements, including synapses; in the hippocampus and cerebral cortex, it gives rise to a greater astrocytic volume associated
with an enhanced number of synapses.
1. Hypothalamoneurohypophysial system
It is now over two decades that electron microscopy
coupled to morphometric analyses of this neuroendocrine
system (74, 181, 185, 192) provided the first clear evidence
that astrocytes are surprisingly dynamic, continually
changing their morphology in relation to the activity of
neighboring neurons.
The hypothalamoneurohypophysial system (HNS) is
composed of magnocellular neurons that secrete either
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OT or VP and that accumulate in well-defined regions of
the hypothalamus, the paired SON and paraventricular
(PVN) nuclei. Their axons project, via the internal layer of
the median eminence, to the neurohypophysis where the
neuropeptides are released directly into the bloodstream.
As a neurohormone, OT intervenes in vital functions like
parturition and lactation while VP is essential to osmotic
and cardiovascular regulation. Both peptides are released
centrally as well, in different regions, where they participate in various neurovegetative and limbic functions (reviewed in Ref. 105). Within the magnocellular nuclei, they
are released mainly by a somatodendritic exocytotic
mechanism (120) and ultimately facilitate the activity of
their own neurons (156). OT and VP neurons respond to
afferent stimulation by increased electrophysiological
and secretory activities, with patterns specific to each
type of neuron (150). At the same time, as shown by
ultrastructural analyses of profiles immunoidentified as
oxytocinergic or vasopressinergic, OT neurons undergo
striking morphological changes. Their somata progressively hypertrophy (reviewed in Ref. 172), their dendrites
change in size and branching (168), and their axons enlarge and ramify (73, 115).
In the hypothalamus, OT neurons usually occur in
tightly packed clusters, but under basal conditions of
neurosecretion, they remain separated by fine astrocytic
processes (Figs. 2A and 6). In contrast, during parturition,
lactation, chronic dehydration, or in response to elevated
ambient levels of OT, there is a significant reduction in the
astrocytic coverage of all portions of OT neurons (reviewed in Ref. 172). In the rat SON, for example, astrocytic processes cover ⬃90% of any OT soma under normal
conditions, a proportion that is reduced to 70% during
lactation or chronic dehydration (26, 174). At the same
time, their surfaces, as that of their dendrites, become
directly and extensively juxtaposed (Fig. 6). Where this
occurs, neuronal membranes do not contact each other,
and the extent of the ECS remains unaltered (Fig. 6,
bottom image). Gap junctions are not visible between
juxtaposed neuronal membranes, but they are detected
between astrocytic profiles (106, 185). Astrocytic coverage of synapses contacting OT neurons is also significantly reduced (138). This plasticity, which has been analyzed in the rat (for a review, see Ref. 172), mouse (187),
and several desert rodents (Ouali and Theodosis, unpublished observations), takes place throughout the hypothalamus, in all the nuclei containing OT neurons. In
contrast, in response to stimulation for VP secretion,
including severe chronic salt loading (26), astrocytic coverage of VP neurons is not altered and remains at ⬃90%.
While VP neurons display some juxtapositions, their incidence is low, they are small, and more importantly, they
show no variation with changing conditions of VP secretion (26, 174).
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FIG. 6. Activity-dependent morphological plasticity of astrocytic
processes in the adult hypothalamus. Electron microscopy (images on
top) coupled to morphometric analyses (bottom) of the rat SON during
different stages of the reproductive cycle revealed that, at parturition
and lactation, when the electrical and secretory activities of OT neurons
are greatly enhanced, there is significant reduction in astrocytic coverage of neuronal somata and dendrites whose surfaces become directly
juxtaposed. Note that juxtaposed neuronal surfaces do not directly
contact each other (lower micrograph and at higher magnification in the
inset). When activity is again reduced (after weaning the young, for
example), the nucleus returns to its original condition and astrocytic
processes again ensheath and separate neuronal profiles. The nucleus
assumes its stimulated morphology upon new activation in the course of
a second parturition and lactation. [Modified from Montagnese et al.
(116) and Theodosis and Poulain (182).]
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Concomitant glial transformations in the neurohypophysis result in a reduced glial ensheathment of the
axons and terminals of these neurons (reviewed in Refs.
72, 176). At perivascular areas, this leads to a significantly
enlarged neurovascular contact zone (Fig. 3). Thus, under
basal conditions, ⬃40% of the perivascular basal lamina is
contacted by neurosecretory terminals and ⬃60% by processes of astrocytic-like pituicytes. During all conditions
that stimulate neurosecretion, there is retraction of
pituicyte processes from the perivascular zone as well as
proliferation of neurosecretory terminals, and these proportions are reversed (Fig. 3) (73, 115).
In vivo analyses had strongly suggested that this form
of glial-neuronal transformation is rapid, since changes
were detected within a few hours of the onset of parturition (117) or osmotic stimulation (192). In vitro analyses
in acute slices of adult hypothalamus that include the
SON (106, 175), or in hemineurohypophyses (115, 145),
show clearly that such glial transformations occur very
rapidly indeed, within 1 h of stimulated neurosecretion.
When OT secretion returns to baseline levels (for example, after weaning the young or reduction of ambient
OT), astrocytic processes reappear between neuronal
profiles, and the structure of the magnocellular nuclei
and neurohypophysis assume their unstimulated morphologies. This phenomenon can take a few hours as
well (106, 115).
Whether juxtaposed neuronal surfaces are due only
to retraction of astrocytic processes is not established.
What is highly unlikely is that the processes are squeezed
away passively by hypertrophied neuronal profiles. For
example, this mechanism does not explain the significant
reduction in astrocytic ensheathing of dendrites and the
appearance of numerous dendritic bundles (see Ref. 184).
The rapidity of the glial changes also precludes such a
possibility, since they can be detected in tissues where
hypertrophy of neuronal elements has not yet occurred
(106). Moreover, VP neurons greatly hypertrophy during
conditions like chronic dehydration, yet their surfaces do
not become increasingly juxtaposed (26). A more likely
explanation is that neuronal juxtapositions are the result
of active retraction and elongation of astrocytic processes over surfaces of neuronal elements whose morphology is constantly changing. The altered expression
of several cytoskeletal proteins in HNS neurons and
glia (75, 114, 133) presumably reflects this remodeling.
Compared with other systems (8), one expects that
these cell transformations are accompanied by differential gene expression and de novo protein synthesis.
In the SON, new macromolecular synthesis is essential,
since there is no glial or neuronal remodeling when
protein synthesis is blocked by agents like anisomycin
(106).
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2. Basal hypothalamus
Rapid, activity-dependent astrocytic remodeling is
detectable in other areas of the basal hypothalamus. In
the rat arcuate nucleus, composed of neurons that secrete
reproductive hormones, the proportion of neuronal somatic surface covered by astrocytic processes fluctuates
in relation with sexual steroid levels, being high when
plasma estrogen is elevated (afternoon of proestrus and
morning of estrus) and low 24 h later at metestrus when
estrogen levels have diminished (reviewed in Ref. 54).
Administration of estradiol to ovariectomized animals
mimics the effects of the estrous cycle and shows that,
like in the SON (106), the astrocytic-neuronal changes are
rapid, occurring within 2 h of steroid injection. Similar
phenomena have been recorded in the infundibulum and
preoptic area of primates, areas analogous to the rodent
arcuate nucleus. Thus, in Rhesus (209) and African green
(54) monkeys, glial ensheathment of gonadotropin releasing hormone (GnRH) neurons varies significantly in relation to steroid levels, a remodeling that is reproducible in
ovariectomized animals given estradiol replacement.
The axons of GnRH neurons project to the external
layer of the median eminence where fluctuating steroid
levels lead to axonal-glial changes similar to those characterizing the neurohypophysis. They result in retraction
of end feet of tanycytes (modified ependymoglial cells)
from the perivascular zone and exposure of GnRH terminals to fenestrated portal capillaries (36, 97). In neurohemal structures, therefore, glial rearrangements ultimately
permit direct access of neurosecretory axons to perivascular zones, an anatomical configuration that will favor
release of neurosecretory products into the circulation.
3. Suprachiasmatic nucleus
Another hypothalamic nucleus that displays astrocytic-neuronal remodeling is the SCN, the master clock
driving circadian rhythm. Earlier work had described pronounced circadian fluctuations in GFAP labeling in the
hamster SCN (108, 109). This was confirmed recently in
the rat where GFAP rhythm appeared closely dependent
on light entrainment (12). By using ultrastructural analysis, the latter study clearly showed that fine astrocytic
processes covering vasoactive intestinal polypeptide
(VIP) and VP neurons continually undergo remodeling.
The changes were closely linked to the light-dark cycle
and were accompanied by altered proportions of directly
juxtaposed somatic and dendritic profiles (12). Taken
together, the observations provide convincing evidence
that in the SCN, modulation of the morphology of astrocytic processes is closely related to the oscillatory activity
of the biological clock synchronizing circadian rhythms to
the 24-h light-dark cycle.
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4. Brain stem
Two-photon microscopy of the brain stem in acute
slices from postnatal transgenic mice have offered direct
proof that astroglial processes display a high degree of
motility (Fig. 7), closely linked to the activity of the
synapses they ensheath (77). The astrocytes were rendered visible by expression of green fluorescent protein
(GFP) and the synapses by uptake of the endocytic
marker FMI-43. Two distinct modes of process motility
were visualized, gliding of thin lamellopodia along neuronal surfaces and transient extensions and retractions of
filopodial processes into the neuronal environment. These
dynamic changes occurred within minutes while the morphology of astrocytic somata remained stable.
5. Hippocampus
Early electron microscopic analyses indicated that
synaptic plasticity or long-term potentiation (LTP) is accompanied by astrocytic remodeling, since an increased
density and closer apposition of astrocytic processes to
the synaptic cleft of potentiated synapses was noted in
the dentate gyrus 8 h after LTP induction in vivo (206).
More recent studies using time-lapse imaging of fluorescently labeled live cells in acute slices have confirmed this
earlier work and revealed that the fine processes of adult
hippocampal astrocytes display motility in situ (13, 68,
126). As the astrocytic processes underwent different types
993
of motility, similar to those visualized in the brain stem (77),
filopodia emerged from astrocytic tips and there was a constant extension and retraction of lamellopodia-like structures, over a time scale of minutes. Even splitting of individual processes was noted (68).
Not unexpectedly, actin-based cytoskeletal rearrangements are involved, and the astrocytic transformations were closely linked to transformations in neighboring neuronal elements. Thus, in rat hippocampal slice
cultures (124, 131), as well as in acute slices (68), repetitive two-photon scanning revealed that astrocytic contacts enhanced both the lifetime and morphological maturation of pyramidal neuron dendritic spines. The motility
of astrocytic processes exceeded that of dendritic filopodia, and the former showed directional protrusive activity
towards dendrites. As will be discussed in more detail
later, such observations strongly suggest that the direction and extent of astrocytic process motility is regulated
by environmental cues, including diffusible factors from
adjacent neuronal elements.
6. Cerebellum
Electrophysiological and morphological observations revealed that rather than engaging in static encapsulation, Bergmann glia require constant input from their
associated synapses to maintain their relationship (83). It
is AMPA receptors on these astrocytes that play the important role of maintaining ensheathment. The Ca2⫹ permeability of AMPA receptors is determined by the presence of the GluR2 subunit, which markedly reduces Ca2⫹
entry into the cells. Removal of GluR2 subunits from
these receptors reduced Ca2⫹ permeability in the cells
and was accompanied by process retraction, leaving synapses uncovered by glia. The phenomenon was accompanied by delayed glutamate uptake (83). In vitro studies
(84) supported these findings and showed that conversion
of AMPA receptors to the Ca2⫹-impermeable type resulted in glial process retraction while overexpression of
Ca2⫹-permeable receptors produced process extension.
On a more general level, it is noteworthy that synaptogenesis induced by motor learning in the cerebellar cortex
was associated with an increased volume of astrocytic
processes, a parameter that remained unaffected by increased neuronal activity due to exercise (90).
7. Barrel cortex
FIG. 7. Live imaging of astrocyte process motility in the adult brain
stem. A confocal display of four consecutive images separated by 2-min
intervals (single optical planes) illustrates spontaneous, transient, and
surprisingly rapid extension of an astrocytic process (position indicated
by red square), visualized in situ in acute slices from GFAP-eGFP
transgenic mice. [Adapted from Hirrlinger et al. (77).]
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In mice, sensory stimulation elicited by 24-h whisker
stimulation caused surprising changes in astrocytic ensheathment of glutamate synapses. In contrast to events
in the rat SON (172), stimulation here resulted in a significantly enhanced astrocytic coverage of axo-spinous glutamatergic synapses (58). This appeared to be due to
remodeling of individual processes over particular spines,
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THEODOSIS, POULAIN, AND OLIET
since there were no changes in the total volume or surface
area occupied by the processes.
8. Neocortex
In acute rat cortical slices, application of brain-derived neurotrophic factor (BDNF) rapidly modified the
morphology of astrocytic processes via T1 activation and
signaling (136). While in other areas astrocytic processes
were seen to extend over very few micrometers (77), in
this study they were noted to extend as far as 15 ␮m.
9. Visual cortex
Quantification of fine astrocytic processes in layers
I–IV of the rat visual cortex indicated changes in their
volume per neuron roughly comparable to the increase
in synapse number recorded after 30 days exposure to
an enriched environment (90, 91). Moreover, the enriched environment enhanced the degree of surface
contact made by fine astrocytic processes with axodendritic synapses, an increase which tended to be greater
in layer IV but which was also apparent in layers I and
II/III. On the other hand, in the cat visual cortex, a
reduced neuronal activity induced by dark rearing during the critical period retarded astrocytic maturation
and resulted in a reduced number of astrocytic processes in the neuropil (122).
B. Consequences on Extracellular Homeostasis
Since astrocytic processes are an important structural element of the space surrounding neurons and
since they serve to maintain the homeostasis of the
ECS, any structural modification of the astrocytic environment should affect the volume and geometry of the
ECS as well as its molecular composition. The rat SON
with its clear lactation-related astrocytic changes has
served to test this possibility directly (148), using the
real-time tetramethylammonium (TMA⫹) iontophoretic
method (130). The approach permits measurement of
diffusion parameters like tortuosity (a measure of restriction on diffusion in the tissue compared with an
obstacle-free medium), volume fraction (the volume of
tissue occupied by the ECS), and nonspecific uptake. In
virgin rats, diffusion in the SON was not equivalent in
all directions (anisotropy), and tortuosity was hindered
less along the ventrodorsal axis, probably reflecting the
ventrodorsal orientation of most large astrocytic processes in this structure (17, 87). On the other hand, in
lactating animals, in which there is remodeling of astrocytic processes (184), there was a significant reduction of volume fraction and tortuosity. As a consequence, diffusion became equivalent in all planes (isotropy), indicating that not only was the geometry of the
Physiol Rev • VOL
ECS affected, but its diffusion properties as well
(Fig. 8). This would then enhance the range of action of
circulating molecules and their local concentrations, a
phenomenon with important repercussions, especially
on neurotransmission.
C. Consequences on Excitatory
and Inhibitory Neurotransmission
Because astrocytic processes carry transporters that
rapidly clear away neurotransmitters like glutamate (Fig.
2, B and C), they control the accumulation and diffusion
of these transmitters in the ECS near the source of their
release. It follows that the positioning of glutamate transporters close to the site of glutamate release is paramount
if they are to remove it efficiently. In the barrel cortex,
two-thirds of spines have astrocytic processes at the bouton-spine interphase. As noted in section IIIA, sensory
stimulation induces these processes to adopt a more
intimate contact with the region through which glutamate transmission occurs, a remodeling that is accompanied by a significantly enhanced expression of the astrocytic glutamate transporters GLAST and GLT1 (58).
These changes ensure that the cortex guards against possible deleterious effects of high concentrations of glutamate in the ECS.
On the other hand, withdrawal of astrocytic processes from the synaptic cleft area has several consequences on synaptic transmission, including modulation
of postsynaptic responses, modulation of feedback mechanisms on afferents, and the appearance of heterosynaptic cross-talk between neighboring synapses (Fig. 8).
Electrophysiological observations obtained in acute
slices of the rat SON have provided direct evidence for
this. Like most CNS structures, the SON contains glutamate afferents that provide excitatory input to both its
neurosecretory populations (47). Compared with virgin
rats, in lactating (138, 147) and chronically dehydrated
(18) animals, in which there are fewer astrocytic processes around OT neurons and their glutamatergic synapses (172) (Figs. 6 and 8), tonic activation of presynaptic
metabotropic glutamate receptors on glutamate synapses
was enhanced, which reduced synaptic efficacy (18, 138).
This effect was similar to that induced by pharmacological blockade of glutamate transporters in virgin rats (147).
Another system in which similar phenomena have been
noted is the cerebellum (83), where retraction of Bergmann glia processes resulted in delayed glutamate uptake
and modified glutamate neurotransmission.
Under certain conditions, accumulation of glutamate
in the ECS may lead to heterosynaptic modulation of
neighboring afferents. At basal levels of glutamatergic
activity, glutamate is not sufficient to activate glutamate
receptors located at a distance from glutamatergic syn-
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995
FIG. 8. Schema illustrating peripheral astrocytic processes between SON neurons and around axonal terminals in unstimulated (for example, virgin and postweaned rats) and stimulated (lactating and dehydrated
rats) conditions of neurosecretion. Under stimulation,
retraction of astrocytic processes favors diffusion (black
arrows) of synaptically released glutamate in the extracellular space, which can then act on the same and/or
adjacent synapses (homo- and heterosynaptic interactions). Note that for the sake of schematic representation, the extracellular space is grossly represented. In
fixed tissues, the extent of space between contiguous
cellular elements is in the range of 10 –12 nm (see Fig. 6).
[Adapted from Theodosis et al. (180).]
apses, an observation consistent with earlier studies (reviewed in Ref. 139). However, heterosynaptic modulation
of GABAergic transmission was noted when glutamatergic input activity was high enough to saturate glutamate
transporters and enable diffusion of glutamate to remote
receptors. In the SON of virgin rats, this heterosynaptic
depression of GABAergic transmission occurred only
when short conditioning trains of stimulation were applied to glutamatergic fibers (147). In lactating rats, because of anatomical remodeling (172) (Fig. 8), a similarly
induced intersynaptic cross-talk was facilitated (147).
Taken together, these observations show that the
presence of astrocytic processes close to the synaptic
cleft enhances point-to-point synaptic communication
and limits presynaptic inhibitory feedback and extrasynaptic communication. Astrocytic process remodeling,
therefore, should be considered an important mechanism
when examining factors that potentially can modify synaptic strength.
D. Effects on Gliotransmission
Repositioning of astrocytic processes will have further consequences on neuronal function, since it affects
Physiol Rev • VOL
the concentration of neuroactive substances secreted by
astrocytes themselves into the ECS. Again, observations
from the hypothalamic magnocellular nuclei provide
clear-cut evidence for this. One such gliotransmitter is
D-serine, present in distal astrocytic processes (Fig. 2, D
and E) and released by activation of glutamatergic receptors to act as a coagonist of glutamate at NMDA receptors
(Fig. 9) (121, 141). In the SON of virgin female rats, under
basal conditions of neurosecretion, there is extensive astrocytic coverage of neuronal elements and the amino
acid almost completely saturates the glycine sites on
NMDA receptors (141). In contrast, in lactating rats, consequent to the considerable withdrawal of astrocytic processes (172), there is a significant reduction in D-serine
levels around synapses (Fig. 9). The occupancy of glycine
sites is then low, and the activity of NMDA receptors is
greatly reduced (141). As a consequence, NMDA receptordependent manifestations of synaptic plasticity, like LTP
and long-term depression (LTD), are profoundly affected.
In particular, the activity dependence of these processes
is shifted towards higher values so that it takes a much
stronger synaptic activity to induce LTP in lactating rats
compared with virgin animals. Since D-serine levels are
reduced in the ECS around synapses, fewer NMDA recep-
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THEODOSIS, POULAIN, AND OLIET
FIG. 9. Schema illustrating the participation of fine astrocytic processes in gliotransmission. In the SON, for example, astrocytically released
D-serine (red squares), together with synaptically released glutamate (gray dots), activates NMDA receptors on postsynaptic elements. Note that
after retraction of astrocytic processes and reduction in glial coverage, there is less D-serine within the synaptic cleft for NMDA receptor activation,
thereby modifying glutamate neurotransmission and plasticity. (Courtesy of A. Panatier.)
tors are activated and, therefore, less Ca2⫹ enters the
postsynaptic neurons. NMDA receptor activity and the
ability to induce LTP and/or LTD in lactating rats are
completely rescued when saturating concentrations of
D-serine are applied to the tissue (141).
A similar scenario occurs in the PVN of dehydrated
rats where the withdrawal of astrocytic processes from
the vicinity of magnocellular neurons (183) affects the
accumulation of yet another gliotransmitter, ATP (64).
The result is insufficient ATP to activate P2X receptors on
the neurons, and synapse strengthening through AMPA
receptor insertion is compromised. This form of synaptic
plasticity can be restored by providing exogenous ATP to
the tissue.
Another consequence of reduced astrocytic coverage
of excitatory synapses may occur via release of cytokines,
like TNF-␣. TNF-␣ released from astrocytic processes
enhances synaptic efficacy by promoting the insertion of
AMPA receptors at neighboring glutamatergic synapses
(11). Its continual presence, therefore, is a prerequisite
for the maintenance of synaptic strength (167). Any
change in TNF-␣ concentration in the vicinity of glutamatergic synapses will modify AMPA receptor number and,
therefore, synaptic strength.
It is obvious, therefore, that by affecting gliotransmission, remodeling of astrocytic processes has far-reaching consequences on glutamatergic transmission and
long-term plasticity (see also Ref. 9).
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E. Astrocytic Changes and Synaptic Remodeling
Astrocytes participate actively in synaptogenesis and
synaptic remodeling in the developing and adult brain,
and their contribution appears complex. On the one hand,
their mere presence along the neuronal surface will hamper the formation of synapses; their absence will allow it.
On the other hand, at least during development, astrocytes favor synaptogenesis by secreting factors that support synapse formation. These include cholesterol and
thrombospondins that promote the formation and maturation of excitatory synapses (29, 112, 194). Moreover,
through their release of substances like TNF-␣, they contribute to subsequent activity-dependent homeostatic establishment of synaptic connectivity (167). Nevertheless,
it remains to be seen whether these secreted factors
intervene in synapse remodeling during adulthood.
Thrombospondin expression, for example, is low or nonexistent in the adult CNS (29).
We have known for decades that synapse formation
with accompanying rearrangements of connectivity occurs
in many adult neuronal systems, in response to a variety of
physiological stimuli. There are many excellent reviews on
this topic (see, for example, Refs. 8, 28, 32, 57), and we shall
limit our discussion to those cases where there appears to
be a participation of astrocytes, direct or indirect.
Several neuroendocrine systems provide clear evidence that certain hypothalamic circuits remain relatively
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plastic throughout life, a plasticity coincident with restructuring of adjacent astrocytes and dependent on the
activity of neighboring neurons. In the magnocellular nuclei of rodents, changes in astrocytic coverage of OT
somata and dendrites invariably occur together with synapse turnover. The most obvious manifestation is the
appearance of boutons making synaptic contact onto
more than one postsynaptic elements simultaneously
(“multiple” synapses) (reviewed in Refs. 172, 188). Similar
synaptic changes are visible in the cerebellum where
retraction of Bergmann glial processes is accompanied by
an increased number of multiple synapses formed by
climbing fibers on Purkinje cells (83). In the OT system,
synaptic density analyses revealed that synapse formation
affects boutons making single synaptic contacts as well.
Moreover, analyses of ultrathin sections in which synapses were immunoidentified as GABAergic, glutamatergic, or noradrenergic allowed to identify the circuits undergoing plasticity as inhibitory (GABAergic) and excitatory (glutamatergic and noradrenergic) (reviewed in Ref.
188). The most important increases affect GABAergic inputs so that in the SON of lactating rats (47, 62), ⬃50% of
all axosomatic and axodendritic synapses are GABAergic,
compared with ⬃35% in the SON of virgin rats under basal
conditions (47). Once stimulation is over, synaptic densities revert to control values. Ultrastructural analyses in
which both pre- and postsynaptic partners were identified
confirmed that the inputs undergoing plasticity are those
impinging on OT neurons (62, 178). This synaptic remodeling can be reproduced in vitro in acute hypothalamic
slices that include the SON. Electron microscopy and
patch-clamp electrophysiology showed that synapse formation is very rapid, occurring within an hour, is reversible within hours as well, and results in the formation of
inhibitory, putative GABAergic synapses that are functional (175).
Another hypothalamic center in which there are synaptic changes clearly linked to astrocytic remodeling is
the arcuate nucleus. In adult females, there is a natural
phasic synaptic turnover that is linked to variations of the
ovarian cycle (54). As clearly demonstrated by ultrastructural analyses, the number of axosomatic GABAergic synapses on arcuate neurons falls significantly between the
morning and afternoon of proestrus, remains low throughout estrus, and rises to baseline levels on metestrus, to fall
again at proestrus. Concurrently, there is increased and
decreased astrocytic ensheathment of neuronal profiles
(55). This negative correlation between the level of glial
ensheathment and number of synaptic inputs in relation
to fluctuations in steroid levels has been detected in primates as well (54, 209). In sheep, on the other hand,
seasonal variations in glial ensheathment and synaptic
inputs occur in the preoptic area. Thus the number of
synapses decreases while astrocytic coverage of neurons
increases between the breeding and nonbreeding seasons
Physiol Rev • VOL
997
in conjunction with the diminished pulsatile GnRH secretion that leads to anestrous (198). In the rodent arcuate,
synaptic rewiring of inhibitory inputs on POMC neurons
has been noted as well, in response to elevated circulating
levels of the hormone leptin, that participates in the regulation of energy balance and growth hormone release
(149). It is not unlikely that these latter synaptic changes
are accompanied by astrocytic changes similar to those
seen in response to estrogen.
An increasing number of reports describe synaptic
transformations linked to changes in glial ensheathment
in brain areas other than the hypothalamus. In the adult
hippocampus, new synapse formation by subsets of
mossy fiber terminals occurs in response to experience
and age (53), while increases in dendritic spine synapses
were noted in response to the hormone ghrelin (41). How
astrocytic processes intervene under such conditions has
yet to be examined, but it is noteworthy that astrocytic
changes were detected in acute hippocampal slices during recuperative synapse formation after synapse loss due
to cutting of the tissue (208). As noted in section IIIA,
astrocytic processes in the hippocampus are capable of a
motility rapid enough to account for these effects (68).
Recent work in different cortical areas offers further
examples of glial participation in adult synaptic plasticity.
This is particularly striking in the barrel cortex, where
whisker stimulation modified astrocytic coverage of glutamatergic synapses and increased the density of putative
excitatory and inhibitory synapses on spines (58). In animals exposed to an enriched environment, the occipital
cortex displays gross changes in thickness, reflecting a
25– 40% increase in dendritic branching, with a parallel
increase in the number of synapses per neuron. Concomitantly, there are changes in the size and surface density
of astrocytes (90).
Most observations of structural synaptic plasticity in
the adult brain concern the appearance of new synapses.
Yet it is clear from studies in neuroendocrine systems that
synapse formation is followed by synapse elimination,
coincident with arrest of stimulation (54, 184). Astrocytes
may promote this synapse elimination as well. Early ultrastructural studies established that astrocytes phagocytose degenerating axonal boutons (1). Recently, a type of
trans-endocytosis was observed between neurons and
astrocytes in culture, which did not resemble this traditional astrocytic phagocytosis of degenerating axons but
rather more fine structural remodeling between neuronal
protrusions and astrocytes (107). Nevertheless, the professional phagocytes of the CNS are microglia (reviewed
in Ref. 70), and it is highly likely that they participate in
remodeling of synaptic connections by engulfing degenerated terminals. This phenomenon has been described in
the rat neurohypophysis (151). It is noteworthy that degenerated synaptic profiles are not detected in the magnocellular or arcuate nuclei of the hypothalamus when
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synaptic densities return to unstimulated levels. In these
structures, then, a reduced number of synapses may reflect a retraction of terminals with concomitant loss of
presynaptic specializations or displacement of terminals
with their presynaptic specializations to neighboring
postsynaptic elements. One expects that intervening astrocytic processes participate in these processes. They cannot
be interposed between pre- and postsynaptic partners if
synapse formation is to occur, whereas their reinsertion
could contribute to the undoing of synaptic contacts (see
also Refs. 1, 54). After synapse elimination, pre- and
postsynaptic protein components may simply be redistributed in their respective compartments, without involving degeneration of boutons.
These possibilities await experimental evidence.
What is certain is that synapse formation must be accompanied by a coordinated development of pre- and postsynaptic molecular and structural specializations, requiring
exchange of information between pre- and postsynaptic
partners, as well as with adjacent astrocytes. As will
be discussed in section VI, astrocytic membranes are
equipped with numerous signaling and cell recognition
molecules (transmitter receptors, transporters, adhesion
molecules) that make the cells well suited for these purposes.
IV. PHYSIOLOGICAL CONSEQUENCES OF
ASTROCYTE-NEURON PLASTICITY
A. Neuroendocrine Regulations
1. Parturition and lactation
The magnocellular system of the hypothalamus constitutes a physiologically controlled system that intervenes in the regulation of several vital neuroendocrine
processes. Its morphological reorganization, described in
earlier sections, involves both its neurons and glia. Since
it is easily accessible in vivo and in vitro, it serves as an
excellent model to analyze the importance of astrocytic
process remodeling, not only at the level of synaptic
function but in the more general context of system physiology as well. This is particularly clear in the case of the
OT system that displays highly characteristic electrical,
biosynthetic, and secretory activities at lactation (reviewed in Refs. 22, 150).
Peripheral information during suckling is transmitted
to OT neurons through nearby glutamatergic neurons.
During the milk ejection reflex, for example, OT neurons
display high-frequency bursts of action potentials (150)
that are triggered by bursts of glutamatergic postsynaptic
potentials derived from a local glutamatergic pulse generator situated in the adjacent hypothalamus (85, 93). As
discussed in section IIIC, patch-clamp recordings provided
Physiol Rev • VOL
convincing evidence that excitatory information transmitted by glutamatergic inputs is affected by glial remodeling
(139). Thus the reduced astrocytic coverage of OT neurons and their synapses during lactation leads to accumulation of glutamate in the ECS. The amino acid, via its
action on metabotropic receptors on those very synapses
from which it is released, will in turn inhibit glutamate
release (138). On first sight, it seems paradoxical that
these inputs exhibit a lower probability of release under a
physiological condition that requires OT neurons to be
strongly activated. However, bursts of action potentials
occur every 5–15 min, separated by periods of low-frequency activity (see Ref. 150). Presynaptic inhibition depends on the level of presynaptic activity (140). The tonic
presynaptic inhibition during the low-frequency period is
likely to be overcome when the probability of release
associated with Ca2⫹ accumulation in the terminals
strongly increases during the brief, high-frequency train of
action potentials occurring at milk ejection. Therefore,
information transmitted via high-frequency excitatory
synaptic activity would be less affected by negative glutamate feedback than information transmitted by low or
moderate frequencies. Such a high-pass filter may serve to
increase signal-to-noise ratio for information carried by
high-frequency activities. It may also favor input from
suckling over other inputs driving OT neurons, such as
those involved in regulating osmotic stimulation and triggering rather low-frequency activity (see below). Moreover, accumulating glutamate in the ECS may exert additional heterosynaptic actions, especially during high-frequency firing. For example, it can inhibit GABAergic
synapses in the vicinity of glutamatergic inputs (148), and
this can lead to a local disinhibition of the somatodendritic compartment (113). The same considerations may
apply to parturition as well, a condition in which OT
neurons display bursting high-frequency discharges (170).
As discussed in detail in section IIID, the presence or
absence of astrocytic processes has important consequences on the ECS concentration of gliotransmitters like
D-serine, which will affect NMDA receptor activation, intracellular Ca2⫹ concentrations, and ultimately, functional synaptic plasticity such as LTP and LTD (141).
During lactation, fewer NMDA receptors are occupied by
D-serine (141), and the threshold for synapse potentiation
is elevated, making it more difficult for synapses to gain
synaptic strength. Making potentiation harder to achieve
may favor very active synapses, like those communicating
the suckling stimulus to OT neurons, while other, less
active, but potentially confounding inputs, will be depressed. Overall, these mechanisms will ensure that the
pool of OT available for secretion will not be used in
response to stimuli not pertinent for parturition or lactation when all available OT will be used for delivery of the
young and milk ejection.
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2. Osmotic regulation
One of the main functions of VP is to contribute to
hydromineral homeostasis by the release of VP acting on
the kidney. OT neurons are also involved in this regulation through the release of OT, inducing sodium excretion
at the level of the kidney (reviewed in Refs. 22, 150). A
puzzling observation is that reduction in astrocytic coverage in the magnocellular nuclei is enhanced during
chronic osmotic stimulation, but specifically in the OT
population (26). However, under such stimulation, OT
neurons display an increased tonic activation, a pattern
different from the periodic bursting activity seen during
suckling (150). As speculated above, in lactating animals,
which are in a state of steady osmotic imbalance (see Ref.
102), it is possible that the astrocytic changes filter out
part of the incoming osmotic stimulus, by a mechanism of
high pass filter. Indeed, OT release in response to osmotic
stimulation is reduced in lactating rats, compared with
virgin rats (102).
Another regulation that could be affected by the astrocytic changes is that related to the release of the
gliotransmitter taurine, an amino acid that contributes to
the control of osmotic balance (81). An altered astrocytic
compartment should modify ECS concentrations of this
amino acid as well, ultimately affecting the activity of
magnocellular neurons via activation of strychnine-sensitive glycine receptors (37) (see also sect. IIID). While this
will be of consequence to the OT population where there
is reduction in astrocytic coverage of neuronal elements,
it should not greatly affect the VP system, in which glial
coverage remains relatively unaltered under these conditions (26). Thus one expects that during a hyposmotic
stress, activation of glycine receptors by taurine will inhibit the activity of OT neurons, thereby promoting diuresis by reducing OT secretion into the bloodstream. On the
other hand, this will be reversed during hyperosmotic
conditions when, due to absence of intervening astrocytic
processes, there is presumably less taurine to activate
glycine receptors, thus allowing enhanced OT secretion
and antidiuresis.
3. Sex-specific behaviors
Another hypothalamic neuroendocrine system where
concurrent astrocytic and synaptic plasticity is of potential import to system activation is that secreting GnRH,
the neurohormone that controls reproductive behaviors
like ovarian cyclicity and puberty. Thus it is highly likely
that the transformations in astrocytic ensheathment of
GnRH somata and dendrites, their synaptic inputs, as well
as GnRH terminals in the median eminence contribute to
the generation of the preovulatory GnRH surge (54, 78,
137). For example, in the rodent arcuate nucleus, most
neurons are hyperpolarized by GABA, and this inhibition
is an important component of the regulation of GnRH and
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999
prolactin release (reviewed in Ref. 54). At proestrus, estrogen enhances astrocytic coverage of GnRH neurons,
and this coincides with a marked reduction in their inhibitory GABAergic synapses (54). A reduced inhibitory input will enhance their firing and therefore increase release of hormone from their terminals into the circulation
just before ovulation. On the other hand, in monkeys,
gonadal steroid-dependent astrocyte-neuron interactions
contribute to the regulation of GnRH secretion at the
onset of puberty (137, 209). Finally, in the rodent ventromedial hypothalamus, it is highly likely that astrocyteneuron interactions participate in the mechanisms controlling sexual behavior, if only to allow synaptic rewiring
taking place under conditions leading to lordosis (52).
4. Circadian rhythm
In the SCN, the biological pacemaker clock driving
and controlling behavioral and physiological circadian
rhythms, the gross changes in the morphology of astrocytes, detected with GFAP labeling (12, 60, 109), have
been associated with fluctuations of serotonergic activation, and it has been suggested that they could be regulated by the daily rhythm of serotonin release (63). On the
other hand, astrocytic modifications have been linked to
glutamatergic afferent activity originating in the retina. It
has thus been proposed that SCN astrocytes regulate and
mediate glutamate release by retinal terminals, thereby
facilitating light signal transmission and contributing to
the coordination of firing of SCN neurons (108). Seasonal
variations have been noted as well (60) and were linked to
alternating photic stimulation conveyed by retinofugal
fibers to the nucleus. It is also noteworthy that there is a
reduced astrocytic coverage of VP neurons in this nucleus
at night, a remodeling which results in increased numbers
of directly juxtaposed dendrites and somata and which
could represent a substrate for nocturnal facilitation of
their synchronized activity (12).
B. Learning and Memory
How plasticity of astrocyte-neuron interactions participates in mechanisms of learning and remembering is
only beginning to be appreciated. Long-term memory
does involve structural rearrangements, especially of synaptic inputs (see, for example, Refs. 8, 90). Synaptic rewiring has been detected in the ocular dominance columns, occipital cortex, cerebellum, and hippocampus and
has been implicated in the control of vision, memory,
motor learning, LTP, and kindling, respectively. One expects that the synaptic changes are accompanied by remodeling of the astrocytic processes with which they are
associated. As illustrated by the hypothalamic magnocellular nuclei (see sect. III), even if the effects of this kind of
remodeling are subtle, they can have far-reaching effects
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THEODOSIS, POULAIN, AND OLIET
on neuronal function and ultimately on the regulation of
phenomena as complex as learning.
VI. CELLULAR MECHANISMS UNDERLYING
ASTROCYTE-NEURON PLASTICITY
V. ASTROCYTE-NEURON INTERACTIONS
AND NEUROPATHOLOGICAL CONDITIONS
A. Permissive Molecular Factors
While the main emphasis in this review has been on
physiological astrocytic-neuronal interactions, one cannot ignore that astrocytes, by their position and because
of their release of neuroactive substances, are potential
sources of pathological conditions as well. Until recently,
for example, they were considered passive bystanders or
victims in conditions like epilepsy, in spite of observations showing that focal epilepsy is accompanied by
pathological changes in astrocytes, including hypertrophy
and hyperplasia (189). In an experimental model of epilepsy, electrophysiological recordings demonstrated that
glutamate release was sufficient to elicit paroxysmal-type
depolarizations in neurons while adjacent astrocytes displayed coincident slow depolarizations of longer duration. These observations thus raise the interesting possibility that epileptiform activity in neurons may initially
activate neighboring astrocytes which then maintain and
propagate neuronal activity independent of synaptic interactions, a mechanism that may explain synchronization of firing during focal seizures.
Another serious neuropathological condition in
which astrocytes appear to be involved is schizophrenia (160). Astrocytes produce factors like Bornea disease virus phosphoprotein which have been linked to
behavioral abnormalities, at least in mice. Psychotic
states which mimic certain aspects of schizophrenia
are elicited by a diminished NMDA neurotransmission,
like that brought on by NMDA antagonists. Clinical
trials using the gliotransmitter D-serine as an agonist of
NMDA receptors revealed partial amelioration of cognitive dysfunction, especially when combined with
classic neuroleptics.
Finally, the emerging literature implicates glia/cytokines in persistent pain. While underlying mechanisms are
still unclear, we know that astrocytes can be activated by
injury, and they release chemical mediators that modulate
neuronal activity and synaptic strength. For example, tissue injury and inflammation in the spinal cord result in
activation of astrocytes and release of proinflammatory
cytokines, while injection of glial and interleukin inhibitors attenuate hyperalgesia and NMDA receptor phosphorylation (190, 205). The data offer strong evidence that
glial activation and inflammatory cytokine release affect
synaptic plasticity through interactions with glutamate
receptors, thus making astrocytes potentially essential
players in the development of inflammatory pain.
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The structural plasticity described in this review connotes dynamic cell-cell and cell-matrix interactions that
bring into play cell surface and ECS molecules, as well as
soluble factors, many of which have been identified by
molecular neurobiology in developing systems undergoing similar glial and neuronal transformations. In the developing brain, the effects of these molecules ultimately
determine the architecture of nervous tissue and are a
result of mutual interactions on the cell surface and activation of intracellular signal transduction mechanisms
through diverse cell surface receptors. It is not too surprising then that adult neural systems capable of remodeling continue to express many of these “juvenile” molecules. The list includes cell adhesion molecules like the
cadherins, ephrins, neurexins, and members of the immunoglobulin superfamily, like NCAM. Complex ECS glycoproteins, like the chondroitin sulfate proteoglycans and
tenascins, as well as their receptors, also contribute (34,
100, 180, 201). Many reviews describe these molecules
and their interactions, especially in the context of axon
outgrowth and synaptic plasticity (see, for example, Refs.
43, 46, 110). Here, we focus on the highly sialylated isoform of NCAM, PSA-NCAM. Our choice is based essentially on the fact that we have direct evidence that this
particular cell surface molecule does intervene in the
dynamic cell interactions responsible for astro-neuronal
remodeling (reviewed in Ref. 180). It thus serves as a good
model to describe the experimental approaches used to
analyze the localization and expression of such molecules
and, in particular, their contribution to cell processes
responsible for morphological plasticity.
While PSA-NCAM is abundant in developing tissues,
most adult tissues contain NCAM with little PSA. However, as we noted in section IIB, it continues to be strongly
expressed in adult systems endowed with the capacity for
morphological plasticity (reviewed in Refs. 15, 16). In the
HNS, for example, PSA-NCAM is made by astrocytes and
neurons throughout life (16, 99, 173, 186). In the hippocampus, PSA-NCAM expression is linked to neuronal
activity (98), but in the HNS (146), as in other neurosecretory systems (80), its expression is constitutive and
not markedly affected by changing conditions of neurosecretion. This does not mean that it is of no consequence
to activity-dependent plasticity. On the contrary, it is a
prerequisite for all its dynamic phases. Thus specific enzymatic removal of PSA from NCAM in the SON in situ
inhibited glial and neuronal remodeling associated with
lactation and chronic dehydration; there was no effect if
PSA was removed once morphological changes had al-
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ready taken place (173). Likewise, enzymatic removal of
PSA from cell surfaces in the neurohypophysis prevented
stimulation-related induction and reversal of axon and
glial changes but had no effect once remodeling had
occurred (115). There is strong, constant expression of
PSA-NCAM in the GnRH system of rodents (16, 80, 162),
sheep (198), and primates (144) where it also appears
essential for astrocytic-neuronal plasticity, since removal
of PSA inhibited the onset of astrocytic and synaptic
changes associated with reproductive status (80, 162).
How PSA intervenes to permit morphological changes
remains undetermined, but a possible mechanism is that
its presence on cell surfaces attenuates adhesion via physical impedance or charge repulsion (159). Cells can then
detach from their neighbors or from the extracellular
matrix and undergo changes in their conformation. In
addition, PSA-NCAM may intervene by transducing intracellular signals resulting in astrocytic shape changes
and/or synapse formation (42).
We consider a molecule like PSA-NCAM permissive
for morphological plasticity in the neuroendocrine centers, since its expression is not tightly linked to neuronal
activity yet it appears obligatory for their morphological
plasticity. This was clearly evident from enzyme perturbation experiments (80, 115, 173). Nonetheless, there can
be compensatory replacement by other molecules, since
remodeling does occur in lactating and salt-loaded transgenic mice genetically deficient in NCAM (187), which
reflects a redundancy in the molecular systems permitting
such plasticity. Similar phenomena have been described
in other neuronal systems in which NCAM is highly expressed and which continue to undergo plasticity in
NCAM ⫺/⫺ mutants (45). In a sense, the specific identity
of molecules permissive for remodeling may not be important provided that they activate the same intracellular
mechanism. On the other hand, the response of neurons
and astrocytes implicated in remodeling would be invariant and independent of the identity of the factor, provided
the proper stimulus intervenes.
B. Signaling Molecules
If molecules like PSA-NCAM act as primers, providing a permissive environment for remodeling, then there
must be molecules whose expression is particular to each
potentially plastic system that act as specific stimuli, capable of triggering cascades of intracellular events that
result in glial and neuronal transformations. As will be
discussed in detail below, such molecules include those
expressed at the onset of enhanced activity to bring on
remodeling as well as molecules, not necessarily identical
to the former, which signal the system to revert to its
original condition. Taking together available observations, there appear to be many candidates for such funcPhysiol Rev • VOL
1001
tions, including neuropeptides, neurotransmitters, steroids, and trophic factors that are released by neighboring
elements and diffuse to astrocytic processes to direct the
extent and direction of the latter’s motility. Nevertheless,
we still have little knowledge of how these signaling
pathways consequently operate, through genomic and
nongenomic pathways, to influence the morphology of the
brain’s cells and its synaptic wiring.
The hypothalamic magnocellular nuclei again offer
many observations that shed some light on the action of
such molecules. In the OT system, the physiological conditions during which astrocytic remodeling is most striking are parturition and lactation (172), conditions characterized by enhanced release of the peptide in the periphery as well as in the hypothalamic nuclei. Intranuclear OT
has a positive-feedback action, since it facilitates the
activity of the OT system (35, 85, 93, 156). It can also
induce its morphological plasticity, since intracerebroventricular infusion of the peptide, presumably mimicking
this central release, induced neuronal-glial and synaptic
changes in the SON similar to those detected under physiological stimulation (177). These effects can be reproduced in vitro, in acute slices of the adult hypothalamus
that include the SON. It was thus possible to show clearly
that the neuropeptide acts specifically via its receptors
since its action was mimicked by close analogs and inhibited with specific OT receptor antagonists (106). Addition
of structurally similar peptides like VP had no effect. The
receptor-mediated action of the neuropeptide may explain why morphological changes in the HNS are specific
to the OT system. In the hypothalamic magnocellular
nuclei, OT receptors occur on OT but not on VP neurons
(10) and on astrocytes (66).
OT, however, does not act alone but in synergy with
sexual steroids, especially estrogen (106, 116). In view of
the rapidity of remodeling (106), it is probable that the
peptide and steroid act via a plasmalemmal mechanism
(155), mobilizing cytosolic Ca2⫹ and inducing signaling
cascades that result in activation of gene expression and
ultimately remodeling. In the magnocellular nuclei, the
steroid does have rapid effects on the electrical activity of
OT neurons (86), and it enhances OT gene expression (33)
and central (202) and peripheral (210) peptide release.
The oxytocin gene promoter, but not the VP promoter,
possesses estrogen-responsive elements (see Ref. 22).
Nevertheless, although OT, with or without steroids, appears essential for remodeling in the magnocellular nuclei, there are other candidates for such signaling, and OT
may act in a secondary fashion, by facilitating their expression.
Of these, glutamate is an excellent candidate, since it
can serve as a bidirectional signal to transfer information
between activated neurons and adjacent astrocytes (see
sect. IIC). In vitro, astrocytes display a rapid structural
response to the amino acid by increasing the number of
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surface filopodia within minutes of its application (31). It
is to be expected then that changes in glutamate transmission may lead to rapid and concerted modifications in
the morphology of neurons and astrocytes. This does
appear to be the case in several brain areas. Thus, in the
cerebellum, activation of AMPA receptors on Bergmann
glia is required for the maintenance of neuron-glia interrelationships (83). In the hippocampus, spine and astrocytic growth and retraction are coordinated in ⬃50% of
cases (68). In the SON, exposure to a combination of
metabotropic and ionotropic glutamate receptor antagonists prevented OT/estrogen-mediated remodeling (106).
Likewise, such a treatment inhibits the appearance of new
GABA synapses (A. Trailin and D. Theodosis, unpublished
observations). In the magnocellular nuclei, then, glutamate itself may be a more immediate signaling agent than
OT. Interestingly, in the hypothalamic preoptic area, a
mediator of astroneuronal communication via glutamate
appears to be prostaglandin E2 (PGE2). PGE2 induces
astrocytic release of glutamate which in turn activates
glutamate receptors on adjacent neurons, an effect which
can have important consequences on neuronal morphology and dendritic spine formation (3).
Another neurotransmitter that may signal glial-neuronal changes is nitric oxide (NO). Electron microscopic
observations of the external layer of the median eminence
indicate that vascular endothelial cells use a signaling
pathway mediated by NO to regulate neuroglial plasticity
(36). Thus activation of endogenous NO release induced a
rapid structural remodeling, resulting in freeing of GnRH
terminals from ensheathing astrocytic processes.
Other excellent signaling candidates are the purines, especially in the neurohypophysis. Neurohypophysial pituicytes possess purinergic receptors (111, 158),
ATP can be released from neurosecretory granules in
the terminals (166), and adenosine, secondary to the
metabolism of ATP, induces pituicyte stellation (114,
158). Activated RhoA GTPase activation is a key event
in coupling purine receptor activation and stellation
(158). In line with these results are preliminary observations of the SON in the acute slice preparation where
adenosine can substitute for OT in inducing astrocytic
and synaptic changes similar to those visible under physiological conditions (A. Trailin, S. Oliet, D. Poulain, and D.
Theodosis, unpublished observations).
Recent studies have revealed that ephrins and their
tyrosine kinase receptors are important intercellular signaling molecules, affecting astrocytic and postsynaptic
structure, at least in the hippocampus. In this brain area,
astrocytes express ephrin A3 and ephrin A receptors
which accumulate on their peripheral processes (124, 126,
191). Activation of neuronal ephrin A receptors induced a
rapid coordinated retraction of dendritic spines and extension of astrocytic filopodia (124), while exposure to
exogenous or endogenous ephrin A gave rise to the outPhysiol Rev • VOL
growth of GFP-labeled astrocytic processes around glutamatergic synapses within minutes (126). Concomitant
with the morphological changes, ephrin A reduced the
frequency of NMDA-mediated currents in CA1 pyramidal
cells, an effect elicited by a diminished glutamate release
from astrocytes (126).
Finally, we have abundant evidence that gonadal steroids themselves signal the onset of morphological
changes, both in the hypothalamus and elsewhere. In the
arcuate nucleus, administration of one single dose of
17␤-estradiol resulting in plasma levels similar to those at
proestrus led to synaptic and astrocytic transformations
similar to those detected at proestrus (54). The effects of
estradiol on arcuate astrocytes were clearly dose-dependent and were blocked by the simultaneous administration of progesterone (54). GnRH neurons themselves do
not express estrogen receptors so that the effects of the
steroid must be mediated through effects on presynaptic
axons and/or astrocytes (209). Indeed, in this area of the
hypothalamus, not only are astrocytes targets for estrogen action, they themselves release factors under the
influence of gonadal steroids that then intervene in morphological rearrangements. Thus estrogens facilitate astrocytic expression of growth factors of the epidermal
growth factor family and their tyrosine kinase receptors,
thereby contributing to neuron-glia signaling implicated
in the initiation of puberty (137). Moreover, astrocytes
and tanycytes in this area release factors like PGE2, insulin growth factor I (IGF-I) and transforming growth factor
(TGF)-␣ that contribute to estrogen-induced synaptic remodeling in the arcuate nucleus and GnRH terminal remodeling in the external layer of the median eminence
(56, 137).
In other central areas, growth factors like BDNF
appear to set off remodeling. In the adult CNS, BDNF is
synthesized and secreted from pre- and postsynaptic neurons in a manner dependent on neuronal activity (see Ref.
104). In slices of adult neocortex (136), activation of T1, a
major BDNF-specific receptor, appears to intervene in the
regulation of astrocyte process morphology via Rho
GTPases. Within 1 h, BDNF induced elongation and
branching of astrocytic processes, while it had no effect when T1 receptors were inactivated. Whether this
occurs in vivo remains to be seen.
C. Cytoskeletal Changes
The intracellular signaling pathway involved in directional motility of fine astrocytic processes has not been
identified. To approach understanding of such mechanisms, many investigators use primary cultures of astrocytes of various sources. Astrocytic processes display
extraordinary capacity for growth and motility in culture,
a phenomenon called stellation (see, for example, Ref.
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PHYSIOLOGICAL ASTROCYTIC-NEURONAL PLASTICITY
158). While this phenomenon may not necessarily be
equivalent to motility of fine astrocytic processes in vivo,
its study does offer clues of the molecular mechanisms
underlying such plasticity.
It is obvious that any kind of morphological plasticity
must depend on rearrangements of cytoskeletal elements.
We have already described dynamic changes in the expression of the intermediate filament protein, GFAP.
There are also effects on tubulin, actin, myosin, and the
ezrin family of actin-binding proteins (20, 38, 39). In particular, myosin enables cell contraction and formation of
cell extensions via its interaction with actin, while ezrin,
a substrate of protein tyrosine kinases, localizes to special
regions of the astrocytic process and cross-links actin
filaments (20, 39). In addition, the Rho subfamily of small
GTPases are major regulators of shape, adhesion, and cell
movements, as are proteins of the protein kinase C family
which inhibit Rho activity (19) and promote extension of
astrocytic processes (27). Recent studies (23, 158) indicate that protein kinase C (PKC) is a key intracellular
regulator of astrocytic remodeling affecting a wide range
of cytoskeletal elements and inactivating Rho A-dependent pathways. For example, adenosine-induced stellation in the neurohypophysis depends on downregulation
of Rho GTPase via F-actin depolymerization and microtubule reorganization (114, 158). Another proposed mechanism involves adenyl cyclase-coupled catecholamine
stimulation of ␤-adrenergic receptors and subsequent enhancement of cytosolic cAMP levels (72).
VII. CONCLUSIONS AND PERSPECTIVES
From the numerous examples offered in this and
other recent reviews (76, 125, 200), it is obvious that the
traditional notion that neurons control all CNS activity
must be revised and that we have to take into account the
active participation of astrocytes in functional neuronal
networks. Moreover, this review has assembled convincing evidence that astrocytes are highly plastic elements in
the adult CNS. This means that dynamic astrocyte-neuron
interactions are part of the physiology of several adult
neuronal systems. A number of hypothalamic neuroendocrine systems, in particular that secreting the neurohormone/neuromodulator OT, illustrate remarkably well the
close association of neuronal and glial activities regulating several homeostatic systems in the body. Similar astrocyte-neuron interactions have now been described
elsewhere in the adult brain, including within the brain
stem, cerebellum, hippocampus, and cortex. Taken together, the observations offer strong evidence that because of their capacity for remodeling, distal astrocytic
processes provide a kind of environmental sensitivity to
synaptic activity that ultimately will influence the overall
activity of the neuronal network.
Physiol Rev • VOL
1003
Given that astrocytic processes appose most synapses in the brain, it is important presently to appreciate
further the extent of this kind of remodeling and to see
whether it is a general phenomenon, coming into play
whenever the proper stimulus intervenes. While a number
of observations provide clues about molecular and cellular mechanisms responsible for such plasticity, we are
still far from a thorough identification and analysis of the
molecular forces driving astrocytic and neuronal transformations, especially those involving lamellate astrocytic
processes that appear devoid of most cytoskeletal elements. Evidence presented in this review indicates that
there are molecules whose expression is permissive for
this kind of plasticity (cell surface adhesion molecules,
ECS components) and that they are common to neuronal
systems that display it. On the other hand, there are
molecules that signal or reverse the morphological
changes (neurotransmitters like glutamate and purines,
neuropeptides like OT, intramembranous proteins like
ephrins and their receptors), and they appear to act specifically in each system that can undergo plasticity. It is
now essential to dissect subsequent intracellular signaling
pathways and to identify genomic and translational mechanisms ultimately resulting in the complex morphological
transformations responsible for coordinated, activity-dependent astrocytic-neuronal remodeling.
ACKNOWLEDGMENTS
We thank S. Lightman and J. Verbalis for their support and
encouragement in the writing of this review and A. Panatier,
J. Tasker, M. Nedergaard, and the Cajal Institute of Madrid for
their generous provision of illustrations.
Address for reprint requests and other correspondence:
D. T. Theodosis, Neurocenter Magendie, INSERM U. 862, 146 rue
Léo-Saignat, Bordeaux F33077, France (e-mail: dionysia.theodosis
@inserm.fr).
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