REVIEWS
NEUROTROPHINS AS SYNAPTIC
MODULATORS
Mu-ming Poo
The role of neurotrophins as regulatory factors that mediate the differentiation and survival of
neurons has been well described. More recent evidence indicates that neurotrophins may also
act as synaptic modulators. Here, I review the evidence that synaptic activity regulates the
synthesis, secretion and action of neurotrophins, which can in turn induce immediate changes in
synaptic efficacy and morphology. By this account, neurotrophins may participate in activitydependent synaptic plasticity, linking synaptic activity with long-term functional and structural
modification of synaptic connections.
Department of Molecular
and Cell Biology, University
of California, Berkeley,
California 94720-3200, USA.
e-mail: mpoo@
uclink4.berkeley.edu
24
The search for target-derived factors that support the
survival and growth of motor and sensory neurons led
to the discovery by Levi-Montalcini, Hamburger and
Cohen1 of the first neurotrophin (NT), nerve growth
factor (NGF). Subsequent studies showed that NGF is
synthesized and secreted by the target tissue2, and that
after binding to its receptors on axon terminals, it is
internalized and transported in a retrograde manner
to the cell body3,4, where it affects neuronal survival
and differentiation.
During development, specific neuronal populations
require the presence of one or more NTs5,6, which now
include NGF, brain-derived neurotrophic factor
(BDNF), NT-3, NT-4/5 and NT-6. The cellular actions
of NTs are mediated by two types of receptor — a highaffinity tyrosine receptor kinase (Trk) and a low-affinity
pan-neurotrophin receptor (p75). Each Trk is preferentially activated by one or more NTs — TrkA by NGF,
TrkB by BDNF and NT-4/5, and TrkC by NT-3 — and
is responsible for mediating most cellular responses7,
whereas p75 forms a complex with the Trk receptor and
modulates its signal transduction8. Binding of the NT
initiates Trk dimerization, transphosphorylation of
tyrosine residues in its cytoplasmic domain and kinase
activation. The phosphotyrosine residues function as
binding sites for recruiting specific cytoplasmic signalling proteins. These proteins may in turnbe activated
by phosphorylation, triggering a cascade of cytoplasmic
effectors that eventually modifies gene expression and
protein synthesis.
Although the long-term trophic effects of NTs
depend on gene regulation, the cytoplasmic effectors
activated by NTs also exert a wide range of more rapid
actions, including morphogenetic9–12 and chemotropic13,14 effects on developing neurons, and modulation of neuronal excitability15,16 and synaptic transmission17–19. This review focuses on the role of NTs as
synaptic modulators for the development and maintenance of synapses and the acute modification of synaptic structure and function. Aspects of this subject have
been covered by several recent reviews20–22.
Activity-dependent expression of neurotrophins
Various NTs are expressed in the nervous system in a
region-specific manner5,6. The level of NT expression is
regulated during development, but persists in many
parts of the adult brain. The most interesting aspect of
NT expression is its sensitivity to electrical activity.
Seizure activity induces a rapid increase in NGF and
BDNF messenger RNA levels in the hippocampus and
the cerebral cortex23–25. Normal physiological activity
that is capable of inducing hippocampal long-term
potentiation (LTP)26,27 also increases the level of BDNF
mRNA. In addition, blockade of visual input results in
a rapid downregulation of BDNF mRNA in the rat
visual cortex and exposing dark-reared animals to light
reverses this change28. Similar effects of electrical activity have also been found in cultured neurons. Neuronal
depolarization by glutamate or by a high concentration
of potassium increases the level of BDNF and NGF
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mRNA29–32 and, in contrast, inhibition of neuronal
activity by GABA (γ-aminobutyric acid) decreases the
level of NT mRNA31,32. Interestingly, neuronal expression of NT-3 or NT-4/5 is not regulated by activity,
although neuromuscular activity downregulates NT4/5 mRNA levels in skeletal muscle33. These findings
indicate that the expression of NTs may be modulated
by neural activity, and in the following sections the
effect of neural activity on the secretion and action of
NTs will be reviewed.
It is generally assumed that NTs are synthesized and
packaged into vesicles in the soma in direct proportion
to the level of their mRNA, and that they are then
transported to either presynaptic axon terminals or
postsynaptic dendrites for local secretion. However, the
level of NTs at synaptic sites may in principle be regulated by two further mechanisms. First, the transport
and targeting of NT-containing vesicles to the synapse
may be regulated. Second, the synaptic level of NTs
may be regulated by local translation of NT mRNAs.
Indeed, ribosomes, elements of the translational
machinery, rough endoplasmic reticulum and the
Golgi apparatus have all been found within dendrites34,35 and there is evidence of local protein synthesis in postsynaptic dendrites in hippocampal slices and
in neurites of cultured neurons36–39. In cultures of dissociated hippocampal neurons, depolarization can elevate the transport of BDNF and TrkB mRNAs to the
a
b
Transport of neurotrophins
Axon
Axon
To soma
Transport
Retrograde
Regulation
Anterograde
To soma
Active NT–Trk
complex in
endocytic
vesicle
Synaptic
vesicle
Trk
receptor
Trk
receptor
Neurotrophin
Neurotrophin
Transmitter
receptor
Secretory
granule
To soma
To soma
Dendrite
Dendrite
Figure 1 | Transport and secretion of neurotrophins. a | The ‘conventional’ route. Following their synthesis in the cell body,
neurotrophins (NTs) and tyrosine receptor kinases (Trks) are transported in secretory granules and post-Golgi vesicles to the
postsynaptic dendrites or presynaptic nerve terminals (not shown). Synaptic activity may regulate the synthesis, packaging and
transport of NTs and Trk receptors. There is also evidence that translation and packaging of NTs and Trk receptors may also occur
locally at the dendrite. The secreted NTs bind and activate Trk receptors in the pre- or postsynaptic membrane, and NT–Trk
complexes are internalized by endocytosis. The endocytic vesicles are shown as parcels of activated plasmalemma that can
propagate transducing activity to distant parts of the neuron by retrograde transport. NT signalling (shown here for autocrine action
on the postsynaptic cell) can also trigger NT secretion. Secreted NTs can modulate presynaptic release of transmitter and
postsynaptic receptor responses after the formation of NT–Trk complexes. b | The ‘unconventional’ route. Endocytic vesicles
containing NT complexes are transported by antero- and retrograde transport to and from the synaptic sites. Activity-dependent
exocytosis of these vesicles allows release of NTs to the synaptic partner. This form of transport provides a mechanism for longrange interneuronal molecular signalling in the neural network without direct involvement of the cell nucleus.
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EPITOPE-TAGGED MOLECULE
A molecule labelled with the
immunological determinant of
an antigen for its subsequent
localization with specific
antibodies.
SYNAPTOSOMES
Discrete particles formed from
the axon terminals upon brain
homogenization, in which the
main structural presynaptic
features are preserved.
COLCHICINE
Alkaloid used to inhibit the
polymerization of tubulin and
cause the depolymerization of
microtubules.
26
neurites, with an apparent increase in the neuritic level
of these proteins36. However, it remains to be established whether the synthesis and packaging of NTs and
Trk receptors can occur in postsynaptic dendrites.
Because there is no evidence for protein synthesis in
mature axon terminals40, the presynaptic level of NTs
and Trk receptors must depend directly on the uptake
of NTs from the extracellular space and the transport
of NT-containing secretory granules and endocytic
vesicles containing NT–Trk complexes to and from the
soma (FIG. 1).
The direction of intracellular transport may provide
clues to the mode of action of NTs. Anterograde axon
transport and accumulation of NTs at axon terminals
are indicative of presynaptic secretion. In contrast, retrograde transport is indicative of uptake by nerve terminals of NTs secreted by the postsynaptic cell.
Although there is evidence for regulated secretion of
NTs (see next section), the identity and characteristics
of the intracellular storage compartment have only
recently been examined in detail. When expressed in
PC12 and AtT-20 neuroendocrine cells, EPITOPE-TAGGED
NTs colocalize with dense-core vesicle markers at both
light and electron microscopic levels41. BDNF was also
found in a vesicular fraction of brain SYNAPTOSOMES42.
These findings are consistent with the idea that NTs are
packaged in a similar manner to conventional secreted
proteins and transported in an anterograde direction to
the nerve terminals. Moreover, immunocytochemical
staining showed that BDNF is widely distributed in
nerve terminals, even in brain areas that lack BDNF
mRNA43,44, such as the striatum, and inhibition of
axonal transport by COLCHICINE or de-afferentation
depletes BDNF in these areas, again suggesting anterograde transport of BDNF. Evidence that the transported BDNF is also secreted and that it exerts trophic
effects on the postsynaptic neuron is provided by
BDNF knockout mice, in which the number of parvalbumin-containing striatal neurons was decreased in
direct proportion to BDNF loss.
Another strong line of evidence for anterograde
transport and secretion of NTs is provided by the
study of interneuronal transfer of NTs in the visual
system. Injection of [125I]-labelled NT-3 into the eye of
chick embryos leads to an uptake of NT-3 in retinal
ganglion cells and anterograde transport to axon terminals. Here, NT-3 is released and taken up by the tectum cell45. This transneuronal transport pathway
requires internalization of NT-3 at both soma/dendrites and axon terminals, secretion at axon terminals,
and transport of NT-3–TrkC complexes in both
antero- and retrograde directions.
Neurotrophins and long-range signalling
Transneuronal transport of NTs raises the important
issue of whether NT–Trk complexes in endocytic vesicles function in signal transduction by providing a
mechanism for long-range signalling in the neuronal
cytoplasm. For sympathetic ganglionic neurons, internalization of NGF–TrkA complexes at axon terminals
and retrograde transport of these complexes to the cell
body is responsible for the NGF-dependent effects on
neuronal survival. However, NGF itself is not the
intracellular retrograde signal because intracellular
injection of NGF does not mimic the NGF-receptor
mediated responses46. The tyrosine kinase activity of
TrkA is required to maintain the complex in an
autophosphorylated state on its arrival in the cell body
and for propagation of the signal to the transcription
factor CREB (cyclic-AMP response element-binding
protein) within the nucleus47,48. Similarly, in the isthmo-optic nucleus (ION) of chick embryos, transport
of BDNF alone did not promote the survival of ION
neurons when axonal TrkB was inactivated49. These
results indicate that endocytic vesicles containing
NT–Trk complexes may be functionally active and
should be viewed as parcels of activated plasmalemma
that spread the cytosolic transducing activity of
NT–Trk complexes to distant parts of the neuron with
the help of active transport (FIG. 1).
So can endocytic vesicles containing NT–Trk complexes be secreted at nerve terminals or postsynaptic
dendrites? Evidence from studies of secretion of false
transmitters from cultured cells suggests that the
answer is positive. Brief incubation of cultured neurons in a solution that contains a transmitter allows
endocytic uptake of the transmitter. Immediately after
incubations, spontaneous quantal release as well as
depolarization-induced release of transmitters can be
detected from either the growth cone or the soma of
the neuron50,51, indicating that endocytic vesicles can
undergo spontaneous and regulated exocytic fusion.
Endocytic vesicles containing NT–Trk complexes may
therefore undergo regulated exocytosis at synapses to
release NTs to the synaptic partner in both antero- and
retrograde directions in an activity-dependent manner, despite the general assumption that endocytic
vesicles derived from the plasma membrane, unlike
post-Golgi secretory granules (containing newly synthesized NTs), are not designated for regulated secretion. Long-range cytoplasmic transport and synaptic
exocytosis of endocytic vesicles containing NT–Trk
complexes provides a means of extensive cytoplasmic
spread and intercellular exchange of molecular signals
within the neural network.
The cellular mechanisms that regulate cytoplasmic
transport of mRNAs and their protein products in
neurons are largely unknown. As discussed above, electrical activity can upregulate NT mRNAs. So does this
activity also affect translation of NT messages and
transport of NTs and Trks? In cultures of dissociated
hippocampal neurons, depolarization elevates dendritic
labelling of BDNF and TrkB mRNA, and increases the
apparent levels of the proteins36. Depolarization and
cAMP elevation can also rapidly recruit TrkB from
internal stores to the plasma membrane of cultured
neurons52,53. Because depolarization-induced exocytosis
of synaptic vesicles is accompanied by elevated endocytosis to retrieve vesicular membrane, it is likely that
receptor-mediated endocytosis involved in the internalization of NT–Trk complexes is also elevated by synaptic activity. If so, synaptic activity may regulate not only
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local NT action at the synapse but also its long-range
global action, through cytoplasmic transport of NT–Trk
complexes (FIG. 1).
Constitutive and regulated secretion
TETANUS TOXIN
Protein from Clostridium tetani
that blocks synaptic exocytosis
of specific synaptic vesicle
proteins, such as synaptobrevin.
VERATRIDINE
Alkaloid that affects action
potential generation by
stabilizing sodium channels in
the open state.
QUANTAL SIZE
The synaptic response elicited by
a single vesicle of transmitter as
determined by postsynaptic
factors such as the number and
affinity of receptors.
DOMINANT-NEGATIVE
MOLECULE
A mutant molecule capable of
interacting with the wild-type
form to make an inactive
complex.
Cellular secretion of protein factors is normally classified as constitutive or regulated depending on whether
the secretion occurs spontaneously or in response to
external stimuli. At present, there is no clear evidence
that ‘true’ constitutive secretion of NTs occurs under
physiological conditions. Moreover, it is difficult, if not
impossible, to fully characterize all of the regulatory signals that a neuron receives under ‘unstimulated’ conditions. So the apparent constitutive secretion may in fact
be regulated. From the cell-biological point of view,
there may be only quantitative differences in the
machinery of exocytosis and the amount of secretion
between these two forms of secretion51. A case in point is
the constitutive secretion of NTs at the synapse. In
Xenopus nerve-muscle cultures, nerve terminals contacting myocytes overexpressing NT-4 showed a higher
frequency of spontaneous quantal acetylcholine (ACh)
secretion than terminals contacting control myocytes,
an effect that could be blocked by the NT-4 scavenger
protein TrkB–IgG54. This suggests that NT-4 is consitutively secreted by the postsynaptic myocyte and that the
secreted NT-4 is responsible for a retrograde modulation of the presynaptic release. An alternative explanation is that the apparent ‘constitutive’ secretion of NTs
by the postsynaptic cell may actually reflect calcium-regulated secretion due to subthreshold depolarization of
the myocyte triggered by spontaneous (action potentialindependent) release of transmitter or other as yet
unidentified factors from the nerve terminal. As discussed in the above section, endocytic vesicles containing NT–Trk complexes undergo exocytosis, resulting in
the transfer of NTs between synaptic partners. There is
also clear evidence that exocytosis of endocytic vesicles
(which are normally classified into constitutive pathways) can be regulated by elevated intracellular calcium
and requires functional TETANUS TOXIN-sensitive proteins
analogous to those associated with synaptic vesicles51. So
all known secretory pathways for NT secretion are likely
to be regulated by synaptic activity or other factors.
Consistent with the regulated secretion of NTs,
BDNF has been found in dense-core vesicles in hippocampal neurons41,42. In hippocampal slices or dissociated
cell cultures, depolarization induced by VERATRIDINE, glutamate, a high level of extracellular potassium or patterned
electrical stimulation results in an elevated level of secreted and/or surface-bound NTs, as revealed by specific
antibodies against NTs55–57. In transfected AtT-20 and
PC12 neuroendocrine cells, secretion of NGF, BDNF and
NT-3 can be triggered by analogues of cAMP or by
depolarization58. Interestingly, the magnitude of BDNF
release from cultured sensory neurons triggered by electrical stimulation was dependent on stimulus pattern,
with high-frequency bursts being most effective57. This is
consistent with the previous finding that secretion of
neuropeptides from the nerve terminal can be induced
only by high-frequency neuronal firing59. It has also been
shown that synaptic activity can trigger post-synaptic
secretion of NTs in Xenopus nerve-muscle cultures. Here,
repetitive synaptic activity induces postsynaptic secretion
of NT-4 from myocytes overexpressing NT-4, which in
turn results in a potentiation of synaptic transmission54.
Finally, NTs themselves can function as the regulatory
signal for NT secretion60,61. Such BDNF-induced secretion of NTs may be mediated by an elevation of intracellular calcium concentration resulting from BDNF–TrkB
signalling in the cell62,63 or direct membrane depolarization induced by BDNF64.
Synapse development and maintenance
Postganglionic fibre axotomy results in a reduction of
synaptic efficacy and eventual withdrawal of preganglionic inputs from the dendrites of ganglionic neurons65. This synaptic loss can be prevented by supplying
exogenous NGF to the axotomized ganglion. The retrograde transport of endogenous NGF seems to be
required for normal maintenance of input synapses on
the dendrite because synaptic loss can be induced by
colchicine, which presumably disrupts microtubulebased axonal transport, or by treatment with antiserum
against NGF65. Although the effects of axotomy on input
synapses are usually examined several days after axotomy, it is possible that NGF molecules transported in a
retrograde manner can produce a more rapid modification of the afferent synapses. For microtubule-based
active transport (at a speed of about 2 µm s–1), it would
take less than an hour for the signal to travel from the
axon terminals to the dendrite located a few millimeters
away. Recent findings of back-propagation of long-term
depression (LTD)66 and LTP67 from the output to the
input synapses of cultured hippocampal neurons indicate the existence of rapid axon–dendrite signalling, in
which target-derived NTs may be involved.
Factors secreted by either pre- or postsynaptic cells
are known to be important in synapse development.
Proteins secreted by motor neurons, such as neuregulin68
and agrin69, can regulate the synthesis and clustering of
postsynaptic ACh receptors, respectively. Conversely,
BDNF, NT-3 and NT-4/5 synthesized by the muscle cells
may act in a retrograde manner on presynaptic motor
neurons, thereby affecting the continued survival and
functional differentiation of the neurons; for example, by
increasing the synthesis of ACh and neuregulin70.
Exogenous BDNF and NT-3 accelerate the maturation of
QUANTAL SIZE and localization of the synaptic vesicle protein synapsin-1 at developing neuromuscular junctions
in cell cultures71,72. Furthermore, muscle-secreted NTs
may act on themselves in an autocrine manner. Disruption of TrkB-mediated signalling by adenoviral infection
of DOMINANT-NEGATIVE (truncated) TrkB in the muscle
resulted in disassembly of ACh-receptor clusters at the
neuromuscular junction73. In the central nervous system,
exogenous BDNF was shown to elevate the expression of
neuropeptides74 and α-amino-3-hydroxy-5-methyl-4isoxazole propionate (AMPA) subtypes of glutamate
receptors75. Overexpression of BDNF in transgenic mice
increases the number of synapses in sympathetic ganglia
and accelerates the maturation of inhibitory pathways in
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the developing visual cortex76. These effects of NTs on
synapse development are likely to be an integral part of
long-term trophic actions involving NT-induced gene
regulation and protein synthesis. Such trophic actions
are also reflected by NT-induced changes in intrinsic
neuronal excitability. In cultured PC12 and neuroblastoma cells, prolonged exposure to NTs can elevate and
differentially regulate the expression of various voltagegated ion channels15,16,77,78.
Acute modulation of synaptic transmission
FILOPODIA
Thin protrusions from a cell,
which usually contain
microfilaments.
28
In cultures of sympathetic neurons or PC12 cells, withdrawal of NGF from the culture medium resulted in a
gradual collapse of FILOPODIA in the neuritic growth cone.
However, the reintroduction of NGF caused the reappearance of active filopodia within one minute9. Because
the growth cone can establish functional synaptic transmission within minutes after contacting the target cell79,
the rapid local action of NGF at the growth cone indicates that NTs may also affect transmission at developing
synapses. Indeed, minutes after applying BDNF or NT-3
(but not NGF) to Xenopus nerve-muscle cultures, both
spontaneous and evoked transmitter secretion were elevated — an effect that persisted for as long as the factor
was present17. Similarly, NGF promotes synaptic transmission between cultured sympathetic neurons and cardiac myocytes80. At central synapses, NTs have been
reported to enhance excitatory synaptic transmission18,19,81–86 and suppress inhibitory transmission86–88 in
both slice and dissociated cell cultures. Most synaptic
effects of NTs are accounted for by presynaptic modification of transmitter secretion, although in three
instances NTs were found to modify the properties of
postsynaptic transmitter channels54,81,89. There is also
some inconsistency in the reported acute effects on
apparently similar systems, which may be due to differences in the preparations and experimental procedures.
For example, in cultured hippocampal neurons, the
magnitude of initial synaptic strength and the nature of
postsynaptic cells are important; the extent of BDNFinduced potentiation of glutamate synapses is inversely
proportional to the initial synaptic strength90,91 and the
potentiation was observed only when the postsynaptic
neuron uses glutamate as a transmitter (rather than
GABA)92. Despite the variation, there is little doubt that
acute synaptic modification by NTs is a widespread
phenomenon in the nervous system.
Modification of transmitter release by BDNF may be
triggered by a BDNF-induced increase in cytosolic calcium62,63 that eventually results in changes in the efficacy of
synaptic vesicle exocytosis93. Recent evidence has implicated synaptic vesicle-associated proteins — synapsin94,
synaptophysin and synaptobrevin93 — as downstream
targets of the BDNF signalling pathway. Acute potentiation of transmitter release was induced by BDNF even
when the soma of the presynaptic neuron was
removed95, suggesting the involvement of only local protein synthesis or post-translational modification of
synaptic components. This is consistent with the finding
of increased phosphorylation of synapsin 1 by BDNF94.
Recently, it was shown that rapid pulsatile application of
TrkB and NT-4 at the neuronal surface can cause membrane depolarization within a few milliseconds64, apparently through TrkB activity-dependent activation of a
novel form of membranesodium channels. So NTs may
not only modulate synaptic transmission, but may also
act as transmitters themselves. This is an intriguing finding that calls for further characterization. Furthermore,
whether physiological stimuli can produce NT secretion
in sufficient amounts and fast enough to result in membrane depolarization needs to be determined.
Neurotrophins are highly basic proteins and bind
tightly to the cell surface or extracellular matrix after
secretion55, and so are likely to act as highly localized
synaptic modulators. At Xenopus neuromuscular
synapses, the potentiation of presynaptic ACh release
and the modification of postsynaptic ACh responses due
to secreted NT-4 from the myocyte were found to be
restricted to within 60 µm of the site of secretion96. The
limited diffusional spread of secreted NTs, together with
the localized distribution of downstream cytosolic effectors, may allow an input-specific synaptic modulation by
NTs after their secretion at the synapse (see section
below on ‘NTs as synaptic morphogens’).
Activity-dependent actions of neurotrophins
Synaptic modulation by NTs depends on a cytoplasmic
signal-transduction cascade, whose efficacy may be
influenced by the presence of electrical activity in the
neuron. This idea is supported by the recent finding that
synaptic potentiation by BDNF is greatly facilitated by
presynaptic activity at developing neuromuscular junctions97. Brief depolarization (or spiking) of the presynaptic neuron in the presence of low BDNF concentration resulted in a marked potentiation of spontaneous
and evoked transmitter secretion, whereas exposure to
either low BDNF concentration or depolarization alone
had no effect. This effect of presynaptic depolarization
was mediated by an elevation of cAMP levels98. So electrically active nerve terminals may be more susceptible
to synaptic potentiation by secreted NTs than inactive
terminals. This may be a useful mechanism for activitydependent synapse refinement. High-frequency neuronal activity and synaptic transmission have been
shown to elevate the number of TrkB receptors on the
surface of cultured hippocampal neurons53, and may
therefore facilitate the synaptic action of BDNF.
Neuronal or synaptic activity is also known to promote
the effects of NTs on dendritic arborization in cortical
slices99 and the survival of cultured retinal ganglion
cells100. In the latter case, the activity elevates cAMP levels
to enhance the responsiveness of the neuron to NTs,
apparently by recruiting extra TrkB receptors to the
plasma membrane52. Although the facilitatory or gating
action of cAMP on NT signalling can occur in the
cytoplasm, such interaction between the NT-dependent pathway and other coincident signals, including
neuronal and synaptic activity, is also important for
long-term trophic effects on gene activation101.
It is of interest to note that the morphogenetic and
chemotropic effects of NTs also depend on coincident
signals that regulate the cytosolic level of cAMP14. For
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example, the guidance of growth cone extension by a
BDNF gradient can be switched between attraction and
repulsion depending on the level of cAMP, which can be
regulated by the presence of extracellular laminin102 or
glutamate14. Preliminary evidence indicates that previous
electrical activity in the neuron may also modulate cAMP
levels (G. Ming and M.-M.P., unpublished observations).
The similarity in the regulatory role of cAMP in synaptic
and morphogenetic actions of NTs suggests common
downstream targets of NT-activated cytoplasmic signals.
a
b
Axon
1
2
3
1
2
3
1
2
3
Dendrite
Figure 2 | Neurotrophins as synaptic morphogens. a | Top: Constitutive secretion of
neurotrophins (NTs) from postsynaptic dendrites results in a low-level of extracellular NTs at the
synapse, which is required for maintenance of normal synaptic function, including the capability
for the induction of long-term potentiation (LTP). Middle: Following intense synaptic activity, a
transient high level of postsynaptic calcium (for example, accompanying the induction of LTP)
results in a high level of NT secretion that raises the local extracellular NT concentration (possibly
corresponding to early-phase LTP). Bottom: High NT levels locally trigger sprouting of nerve
terminal arbors and dendritic spines, leading to the formation of new synapses (possibly
corresponding to late-phase LTP). b | The NT hypothesis for activity-dependent refinement of
connections. Top: Synapses made by the terminals of different axons co-innervating the same
postsynaptic dendrite are maintained in a normal functional state by the low-level constitutive
secretion of NTs. Middle: Correlated activity in axon 1 and axon 2 causes large postsynaptic
depolarization (and spiking) immediately following synaptic activation at axon 1 and axon 2,
resulting in a transient high level of calcium and a high level of NT secretion. By contrast,
uncorrelated activity in axon 3 does not experience postsynaptic spiking at the time of its synaptic
activation, and therefore does not secrete high levels of NT. Bottom: Terminals of axon 1 and axon
2 sprout and new spines are formed in response to local high levels of NT. The synapse made by
axon 3 may lose its postsynaptic supply of NT, owing to the directed transport of
NT-containing granules towards adjacent synapses with correlated activity, leading to synaptic
weakening and eventually withdrawal of the nerve terminal.
Neurotrophins and LTP/LTD
The activity-dependent secretion of NTs and their acute
modulatory effects on synaptic efficacy suggest that NTs
may be responsible for activity-induced LTP or LTD.
Genetic deletion of BDNF in mice disrupted normal
induction of LTP in the CA1 region of the hippocampus
— a defect that was rescued by reintroducing BDNF by
transfecting hippocampal slices with BDNF-expressing
adenovirus or by supplying exogenous BDNF103,104.
Moreover, chelating endogenously secreted BDNF with
TrkB–IgG or antibodies against BDNF reduces
LTP105–107. Does acute synaptic potentiation by secreted
BDNF account for LTP? An early report19 that exogenously-applied BDNF can potentiate basal synaptic
transmission in the CA1 region of the hippocampus has
not been confirmed by other similar studies, suggesting
that BDNF does not mediate CA1 LTP directly. Instead,
BDNF seems to be a permissive factor that is required
for the induction, expression or maintenance of LTP.
This is supported by the finding that BDNF reduces
tetanus-induced depression of transmitter release at
CA3–CA1 synapses of young rats, allowing sufficient
postsynaptic activation for the induction of LTP105.
Unlike factors that are simply required for ‘housekeeping’ functions at the synapse, however, BDNF
expression in the CA1 region of the hippocampus is
rapidly and selectively upregulated during contextual
learning in rats108, and mice lacking TrkB show deficits
in hippocampus-dependent learning tasks. Exogenous
BDNF was also found to block LTD induced by lowfrequency stimulation and enhanced tetanus-induced
LTP in slices of visual cortex109–111, without affecting
basal synaptic transmission. BDNF is required for the
maintenance of late phase potentiation (L-LTP) in the
CA1 region of the hippocampus after the induction of
LTP106,112. The most parsimonious explanation of all
the evidence reviewed above is that in both the CA1
region of the hippocampus and the visual cortex, NTs
seem to modulate the capability of the synapse to
undergo LTP/LTD rather than mediate changes in
synaptic efficacy. However, as discussed below, one
intriguing possibility is that NTs may modulate synaptic morphology in an activity-dependent manner, an
action that is critical for the development of L-LTP and
long-term memory formation.
Neurotrophins as synaptic morphogens
The increased spine density113 and the appearance of
new spines114,115 or multiple spine synapses116 following
the induction of hippocampal LTP are reminiscent of
the morphogenetic action of exogenous NTs on both
axons10,12 and dendrites11.When polystyrene beads coated with NGF or BDNF were placed in direct contact
with the developing neurites of sensory neurons in culture, new collateral sprouts were induced locally at the
contact site within 30 minutes10. NTs secreted by the
postsynaptic cell are likely to be highly localized owing
to their propensity to bind to the cell surface near the
secretion site. By this account, endogenous NTs, secreted
in response to synaptic activity, may induce the morphological changes that lead to the formation of new
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synaptic contacts, as part of the cellular transition from
early to late phase LTP. In the model outlined below, the
synaptic actions of NTs consist of two modes (FIG. 2a). In
the resting ‘permissive’ mode, NTs are secreted at lowlevel through constitutive secretion or regulated secretion triggered by subthreshold and low-frequency
synaptic activity. This permissive mode provides trophic
regulation of synaptic functions, including the ability to
generate LTP. In the active ‘instructive’ mode, NTs are
secreted at a higher level in response to intense synaptic
activity (for example, a tetanus or correlated pre- and
postsynaptic spiking that can induce LTP) that results in
a transient high-level calcium concentration in the postsynaptic cytoplasm. The secretion of NTs may be supplemented by activity-dependent synthesis and transport of NTs. According to the model, high levels of NTs
may then induce the modification of synaptic functions
and the formation of new synaptic contacts.
Electrical activity is critical in the refinement of
developing synaptic connections, as first shown by the
effect of visual deprivation on the segregation of thalamocortical connections117. The hypothesis that activitydriven segregation is based on competition between coinnervating nerve terminals for target-derived trophic
factors118 is supported by recent experimental evidence119–122. For example, local infusion of excess BDNF
or NT-4/5 in the primary visual cortex120, or the removal
of endogenous NTs by infusion of TrkB–IgG122, prevented segregation of thalamic afferents. The critical factor
in the segregation of these afferents is believed to be the
correlation of activities in the co-innervating terminals:
Activities are more correlated for afferents carrying
information from the same eye than those from different eyes. Terminals with correlated activity are stabilized
or strengthened, whereas those with uncorrelated activity (or correlated activity with negative intervals123) are
weakened or eliminated, resulting in sharpening of the
segregation of the afferents for the two eyes. For NTs to
selectively stabilize or strengthen connections with correlated activity, the morphogenetic action of NTs must
be tightly regulated in accordance with the correlated
activity (FIG. 2b). Here I assume that the secretion and
the action of secreted NTs are synapse-specific, because
of the ‘stickiness’ of these highly basic proteins.
Moreover, morphogenetic high-level NT secretion can
only be triggered by transient high levels of calcium —
those that normally accompany the induction of LTP. So
only correlated activities can raise the postsynaptic calcium concentration to a level sufficient to trigger highlevel NT secretion, through cooperative action in postsynaptic membrane depolarization (spiking) at a time
coincident with the synaptic activation. Inputs with
uncorrelated or correlated activity with negative intervals123 fail to raise the postsynaptic calcium concentration, and so are deprived of NTs and eventually withdrawn. The deleterious effect may result from
cytoplasmic depletion of NT supply due to addition of
adjacent new synapses. By assuming that a highcalcium
concentration is needed for postsynaptic secretion of
morphogenetic levels of NTs and that the secretion and
action of NTs are localized, this model links the induction
30
of LTP (with stringent temporal requirement of tens of
milliseconds123) to the slow morphogenetic action of
NTs (on the order of minutes). As functional modulators, secreted NTs can then exert prolonged effects on
presynaptic transmitter secretion or postsynaptic
responses. As morphogenetic modulators, NTs can
modify the structure of existing synapses and induce
formation of new synaptic contacts.
Concluding remarks
The modulatory roles of NTs in synaptic function and
plasticity are now well established, but the underlying
cellular mechanisms are poorly understood. The rapidity of functional modulation by NTs (on the order of
minutes) suggests the involvement of post-translational
modifications of pre-existing synaptic components by
cytoplasmic effectors of the NT-induced signalling cascade. The effects of NTs on synaptic efficacy and neuronal morphology are similarly regulated by electrical
activity and cAMP-dependent pathways, further suggesting common cytoplasmic effectors activated by NTs.
In line with the idea of the dynamic synapse, by which
morphological changes at the synapse are intimately
linked to synaptic functions, the morphogenetic and
functional modulation by NTs may reflect two facets of
the same NT signalling events.
A critical unresolved issue is the synapse specificity
of NT action, the basic assumption underlying the
model shown in FIG. 2b. It is well established that synaptic activity can regulate the expression, secretion and
action of NTs, but it is not clear whether the regulation
of NT synthesis can occur locally only at the active
synapse, and whether the secretion and action of
secreted NT are restricted to the secretion site.
Similarly, it is not known whether regulation of cytoplasmic transport and membrane insertion of Trk
receptors can be synapse specific. At the mechanistic
level, how do NTs achieve local synapse-specific
actions, while fulfilling their global roles in long-range
signalling and trophic actions on neuronal survival and
function? Are cytosolic effectors of Trk receptors effectively localized in the neuronal cytoplasm? Is the global
action of NTs simply a spread of local effectors by cytoplasmic transport of active NT–Trk complexes
throughout the neuron? How are synapse-specific
actions preserved in the presence of the global effects of
NTs? These issues are relevant not only to the elucidation of the neurobiological functions of this particular
family of synaptic modulators, but also to our understanding of general cell-biological principles of signal
transduction and propagation in the cytoplasm.
Links
DATABASE LINKS NGF | BDNF | NT-3 | NT-4/5 | NT-6 |
p75 | TrkA | TrkB | TrkC | CREB | neuregulin | agrin |
synapsin | synaptophysin | synaptobrevin
ENCYCLOPEDIA OF LIFE SCIENCES Axon transport |
Neural activity and the development of brain circuits |
Long-term potentiation | Long-term depression and depotentiation | Dendrites | Trophic support
| JANUARY 2001 | VOLUME 2
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Acknowledgements
I thank A. Schinder and B. Benedikt for helpful discussions and
comments. Work in the author’s laboratory was supported by a
grant from NIH.
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