DOI: 10.1126/science.1209236
, 623 (2011);334Science
, et al.Victoria M. Ho
The Cell Biology of Synaptic Plasticity
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50. D. D. Bock et al., Nature 471, 177 (2011).
51. V. Jain, H. S. Seung, S. C. Turaga, Curr. Opin. Neurobiol.
20, 653 (2010).
Acknowledgments: We thank K. Briggman, H. Hess, J. Livet,
M. Helmstaedter, and S. Smith for providing images and
A. Karpova for commenting on the manuscript. Our own
work was supported by the NIH, Gatsby Charitable
Foundation, and a Collaborative Innovation Award (no.
43667) from Howard Hughes Medical Institute (J.W.L.),
the Deutsche Forschungsgemeinschaft (W.D.), and the
Max-Planck Society (W.D.). W.D. has provided a technology
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10.1126/science.1209168
The Cell Biology of Synaptic Plasticity
Victoria M. Ho,1
Ji-Ann Lee,2
Kelsey C. Martin2,3,4
*
Synaptic plasticity is the experience-dependent change in connectivity between neurons that
is believed to underlie learning and memory. Here, we discuss the cellular and molecular
processes that are altered when a neuron responds to external stimuli, and how these alterations
lead to an increase or decrease in synaptic connectivity. Modification of synaptic components
and changes in gene expression are necessary for many forms of plasticity. We focus on
excitatory neurons in the mammalian hippocampus, one of the best-studied model systems
of learning-related plasticity.
T
he circuitry of the human brain is composed
of a trillion (1012
) neurons and a
quadrillion (1015
) synapses, whose connectivity
underlies all human perception, emotion,
thought, and behavior. Studies in a range
of species have revealed that the overall structure
of the nervous system is genetically hardwired
but that neural circuits undergo extensive
sculpting and rewiring in response to a variety
of stimuli. This process of experience-dependent
changes in synaptic connectivity is called synaptic
plasticity.
Studies of synaptic plasticity have begun to
detail the molecular mechanisms that underlie
these synaptic changes. This research has examined
a variety of cell biological processes, including
synaptic vesicle release and recycling,
neurotransmitter receptor trafficking, cell adhesion,
and stimulus-induced changes in gene expression
within neurons. Taken together, these
studies have provided an initial molecular biological
understanding of how nature and nurture
combine to determine our identities. As a result,
research on synaptic plasticity promises to provide
insight into the biological basis of many
neuropsychiatric disorders in which experiencedependent
brain rewiring goes awry.
Here we focus on long-lasting forms of plasticity
that underlie learning and memory. We
consider, in turn, each component of the synapse:
the presynaptic compartment, the postsynaptic
compartment, and the synaptic cleft, and discuss
processes that undergo activity-dependent modifications
to alter synaptic efficacy. Long-lasting
changes in synaptic connectivity require new
RNA and/or protein synthesis, and we discuss
how gene expression is regulated within neurons.
We concentrate on studies of learning-related
plasticity at excitatory chemical synapses in the
rodent hippocampus because these provide extensive
evidence for the cell biological mechanisms
of plasticity in the vertebrate brain. Space
constraints prevent us from addressing any single
mechanism in depth; instead, our aim is to
provide a framework for understanding the cell
biology of synaptic plasticity.
Hippocampal Synaptic Plasticity
The successful study of the cell biology of synaptic
plasticity requires a tractable experimental
model system. Ideally, such a model should consist
of a defined population of identifiable neurons
and be amenable to electrophysiological,
genetic, and molecular cell biological manipulations.
Awell-studied model system for studying
plasticity in the adult vertebrate nervous system
is the rodent hippocampus (Fig. 1). Critical for
memory formation, the anatomy of the hippocampus
renders it particularly suitable for electrophysiological
investigation. It consists of three
sequential synaptic pathways (perforant, mossy
fiber, and Schaffer collateral pathways), each
with discrete cell body layers and axonal and
dendritic projections (Fig. 1). Synaptic plasticity
has been studied in all three hippocampal pathways.
Distinct stimuli elicit changes in synaptic
1
Interdepartmental Program in Neurosciences, University of
California–Los Angeles (UCLA), BSRB 390B, 615 Charles E.
Young Drive South, Los Angeles, CA 90095–1737, USA. 2
Department
of Biological Chemistry, UCLA, BSRB 310, 615
Charles E. Young Drive South, Los Angeles, CA 90095–1737,
USA. 3
Department of Psychiatry and Biobehavioral Sciences,
UCLA, BSRB 390B, 615 Charles E. Young Drive South, Los
Angeles, CA 90095–1737, USA. 4
Brain Research Institute,
UCLA, BSRB 390B, 615 Charles E. Young Drive South, Los
Angeles, CA 90095–1737, USA.
*To whom correspondence should be addressed. E-mail:
kcmartin@mednet.ucla.edu
Dentate gyrus
Record
Stimulate
CA3
CA1
Perforant (axons from
entorhinal cortex)
Mossy fiber
(axons from dentate
granule cells)
Schaffer collateral
(axons from CA3
pyramidal cells)
Synaptic pathways
Fig. 1. Hippocampal synaptic plasticity. The rodent hippocampus can be dissected and cut into transverse
slices that preserve all three synaptic pathways. In the perforant pathway (purple), axons from the
entorhinal cortex project to form synapses (yellow circles) on dendrites of dentate granule cells; in the
mossy fiber pathway (green), dentate granule axons synapse on CA3 pyramidal neuron dendrites; and in
the Schaffer collateral pathway (brown), CA3 axons synapse on CA1 dendrites. The dentate, CA3, and CA1
cell bodies form discrete somatic layers (dark blue lines), projecting axons and dendrites into defined
regions. Electrodes can be used to stimulate axonal afferents and record from postsynaptic follower cells,
as illustrated for the Schaffer collateral (CA3-CA1) pathway.
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efficacy; high-frequency stimuli produce
synaptic strengthening called
long-term potentiation (LTP), and
low-frequency stimulation produces
synaptic weakening, called longterm
depression (LTD). LTP and
LTD can also be produced by spike
timing–dependentplasticity,in which
the relative timing of pre- and postsynaptic
spikes leads to changes in
synaptic strength (1). Different patterns
of stimulation elicit changes in
synaptic strength that persist over various
time domains, with long-lasting
forms, but not short-term forms, requiring
new RNA and protein synthesis
(2).
Hippocampal plasticity is studied
in in vivo and in vitro preparations.
Implanted electrodes can be used to
stimulate and record from hippocampal
pathways in living animals. The
hippocampus can be dissected out
of the brain and cut into 300- to 500mm-thick
transverse slices that can
be maintained and recorded from
for hours (Fig. 1). Slices can also
be kept as organotypic slice cultures
for weeks, preserving many aspects
of their architecture. Finally, hippocampal
neurons can be studied in
dissociated cultures, which are particularly
amenable to manipulation
and dynamic imaging of individual
neurons and synapses. The development
of genetically modified
mice and vectors for acute manipulation
of gene expression complete
a rich tool-kit for studies of the cell
and molecular biology of hippocampal synaptic
plasticity.
Presynaptic Mechanisms of Plasticity
Communication at chemical synapses involves
the release of neurotransmitter from the presynaptic
terminal, diffusion across the cleft, and
binding to postsynaptic receptors (Figs. 2 and
3). Chemical neurotransmission is rapid (occurring
in milliseconds) and highly regulated. The
presynaptic terminal contains synaptic vesicles
filled with neurotransmitter and a dense matrix
of cytoskeleton and scaffolding proteins at the
site of release, the active zone. Varying the probability
of neurotransmitter release provides one
mechanism for altering synaptic strength during
neuronal plasticity.
Synaptic vesicle release can be subdivided
into distinct steps, including vesicle mobilization,
docking, priming, fusion, and recycling. Although
each of these steps may be regulated by activity,
we will highlight three: vesicle mobilization,
docking, and priming.
Synapsins and synaptic vesicle mobilization.
The population of synaptic vesicles within a presynaptic
terminal exist in three states: the readily
releasable pool docked at the active zone; the
recycling pool, which can be released with moderate
stimulation; and the reserve pool, which is
only released in response to strong stimuli. A family
of phosphoproteins called synapsins tether
synaptic vesicles to the actin cytoskeleton and
to one another. Neuronal stimulation activates
kinases that phosphorylate synapsins to modulate
synaptic vesicle tethering and thereby alter the
number of synaptic vesicles available for release
(3). Synapsin knockout mice have reduced reserve
pools of synaptic vesicles and demonstrate
deficits in learning and memory as well
as various forms of plasticity (4), indicating that
activity-dependent modulation of synaptic vesicle
mobilization is critical to neuronal and behavioral
plasticity.
RIM proteins and synaptic vesicle docking
and priming. For synaptic vesicles to become
fusion competent, they must undergo docking
and priming, in which vesicle and plasma membrane
soluble NSF-attachment protein receptor
(SNARE) proteins are brought into close contact
to allow rapid fusion following calcium influx.
The Rab3-interacting molecule (RIM) family
of proteins is critical for this process (5). As
large, multidomain proteins, RIMs act as scaffolding
proteins to cluster calcium channels in the
active zone (6) and interact with Munc-13 (7),
a priming factor required for efficient SNARE
complex formation and membrane fusion. RIM
is a substrate for phosphorylation by protein kinase
A (PKA) and is required for mossy fiber
LTP (8).
Postsynaptic Mechanisms of Plasticity
Most principle neurons in the brain are studded
with membrane protuberances called dendritic
spines, which are the postsynaptic compartments.
Spines are heterogeneous in shape (Fig.
2), but consist of a bulbous head and a thinner
neck that connects the spine to the dendritic
shaft; the size of the spine head and the volume
of the spine correlate with synaptic strength
(9, 10), with large spine heads containing more
neurotransmitter receptors, reflecting greater synaptic
strength. Spines serve as compartmentalized
signaling units, and the number and shape
of spines change during synaptic plasticity (11).
At the ultrastructural level, the postsynaptic compartment
is characterized by an electron-dense
postsynaptic density (PSD), which consists of
neurotransmitter receptors and an extensive network
of scaffolding proteins.
Activation of postsynaptic kinases in the
spine: CaMKII and PKMz. LTP and LTD induction
are both dependent on postsynaptic increases
in intracellular calcium, with LTP requiring large
increases in calcium concentrations and LTD
being dependent on smaller calcium increases.
The increase in calcium activates multiple downstream
signaling enzymes, including the kinases
calcium/calmodulin-dependent protein kinase II
(CaMKII) and protein kinase C (PKC).
LTP induction in the CA1 region of the hippocampus
requires CaMKII activity (12, 13),
and transgenic mice lacking the a isoform have
defective LTP and spatial learning (14, 15).
CaMKII undergoes autophosphorylation in response
to increases in Ca2+
-bound calmodulin,
which renders the kinase autonomously active.
Neuronal activity also translocates CaMKII to
the PSD, where it can phosphorylate many PSD
proteins, including glutamate receptors. The autophosphorylation
of CaMKII is essential for LTP
induction and, perhaps, its maintenance (16) [but
see (17)].
The brain-restricted atypical PKC isoform,
protein kinase M zeta (PKMz), is constitutively
active and thus phosphorylates targets in the absence
of extracellular stimulation. PKMz mRNA
is targeted to dendrites where activity-dependent
signaling cascades regulate its local translation
during LTP and LTD (18). PKMz is sufficient
and necessary for LTP maintenance and for the
maintenance of long-term memories, and PKMz
activation may perpetuate synaptic plasticity and
memory (18, 19).
Activity-dependent modulation of postsynaptic
glutamate receptors. The main excitatory
neurotransmitter in the brain is glutamate, which
Fig. 2. The ultrastructure of the synapse. Neurons communicate
with one another at chemical synapses. (A) Electron micrograph
from area CA1 in adult rat hippocampus. The CA1 dendritic shaft
is colorized in yellow, the spine neck and head in green, the
presynaptic terminal in orange, and astroglial processes in blue.
Scale bar, 0.5 mm. (B) Three-dimensional reconstruction of an
8.5-mm-long dendrite (yellow) with the PSDs labeled in red. Note
the variation in spine and PSD size and shape. Scale cube, 0.5 mm3
.
Reproduced with permission from Elsevier (63).
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activates several postsynaptic receptors. Two types
of ionotropic glutamate receptors—a-amino-3hydroxy-5-methyl-4-isoxazolepropionic
acid
(AMPA) and N-methyl D-aspartate (NMDA)—
have central roles in hippocampal synaptic plasticity.
Both are ligand-gated ion channels and
have unique properties that subserve different
phases of synaptic plasticity. NMDA-type glutamate
receptors (NMDARs) are calcium permeable
and, when activated, allow an influx of
calcium needed for the induction of LTP. However,
NMDARs do not conduct current at resting
potentials because their channel pores are blocked
by magnesium cations. Consequently, NMDARs
have been called “coincidence detectors” because,
to conduct current, they require both presynaptic
transmitter release as well as postsynaptic depolarization
to relieve the magnesium block.
AMPA-type glutamate receptors (AMPARs) are
important for the expression and maintenance
of LTP. Unlike NMDARs, AMPARs can be activated
by ligand binding at resting potentials
to allow current flow. Increased conductance
through AMPARs is responsible for the increase
in synaptic strength during NMDAR-dependent
LTP at CA1 synapses.
Given the importance of AMPARs in determining
synaptic strength, much effort has
focused on delineating the mechanisms that
regulate their function. Regulated phosphorylation
can change AMPAR function by changing
the open probabilities and conductances of the
receptors. However, changes in channel properties
are unlikely to account for the drastic changes
in AMPAR function seen with LTP (20). Instead,
changes in AMPAR function during synaptic plasticity
are mostly due to phosphorylation-induced
changes in its abundance at the synapse.
AMPARs traffic constitutively to and from
the plasma membrane via recycling endosomes
(21) (Fig. 3). Delivery of AMPARs to synapses is
believed to occur first by exocytosis at extrasynaptic
sites followed by lateral diffusion within
the plasma membrane to PSDs, where the mobility
of the receptors is greatly reduced. During
removal of synaptic AMPARs, receptors diffuse
away from the PSD and then undergo clathrinmediated,
dynamin-dependent endocytosis. After
endocytosis, small GTP-binding proteins of the
Rab family and effector proteins direct AMPARs
either to early (sorting) endosomes or back to
the plasma membrane (22).
AMPAR trafficking occurs constitutively under
basal conditions and is modulated by activity
through changes in actin and myosin dynamics
(23), as well as AMPAR interactions with scaffolding
proteins and accessory subunits. One of
these accessory subunits, Stargazin, mediates the
interaction between AMPARs and the PSD protein
PSD-95, and this interaction is important
for synaptic localization of AMPARs (24). Activity
alters the phosphorylation of Stargazin,
with phosphorylated Stargazin decreasing the
5
P
Internal sources of AMPARs
Degradation
Endocytosis
Presynaptic
axon
terminal
Postsynaptic
dendritic
spine
Synaptic
cleft
Synaptic
cell adhesion
molecules
VSCC
Fusion
and exocytosis
EphrinB
EphB
Endocytosis
Synaptic
vesicle
Neurotransmitter
uptake
Neurotransmitter
molecules
AMPAR
AMPAR
NMDAR
PSD
1
Exocytosis
3
b
c
Neurexin
Neuroligin
NCAM
NCAM
PSA-
NCAM
PSA-
NCAM
2
Lateral
diffusion
4
Vesicle
mobilization
Active zone 6Docking
and priming
a
Fig. 3. Activity-dependent modulation of pre-, post-, and trans-synaptic
components. Presynaptic: Neurotransmitter vesicle cycling. Neurotransmitter
release starts with the filling of synaptic vesicles, which then dock and
undergo priming at the active zone. Arrival of an action potential induces
calcium influx through voltage-sensitive calcium channels (VSCCs), which
triggers membrane fusion and exocytosis. The synaptic vesicles are then
recycled via local reuse (a; “kiss and stay”), fast recycling (b; “kiss and
run”), or clathrin-mediated endocytosis (c). Neurotransmitter release can be
regulated during plasticity as exemplified by the regulation of synapsin
phosphorylation (1) and the regulation of RIM protein phosphorylation
(2). Postsynaptic: AMPA receptor trafficking. Locally and somatically synthesized
AMPARs enter a pool of endosomes that undergo constitutive
and regulated membrane trafficking. During potentiation, greater receptor
insertion (3) increases the concentration of AMPARs at the synapse, where
they are anchored by interactions at the PSD. During synaptic depression,
AMPARs are endocytosed (3). The preferential location of endocytosis and
exocytosis is probably extrasynaptic. Within the plasma membrane, trafficking
of AMPARs between the synapse and the point of insertion or removal
occurs by lateral diffusion. Extrasynaptic movement of AMPARs increases
with neuronal activity (4). Receptor trafficking is modulated by phosphorylation
of AMPAR subunits (5), which influences interactions with scaffolding
proteins. Trans-synaptic: Synaptic cell adhesion molecules. PSA-NCAM is
increased following neuronal activity (6). Lightning bolts indicate activitydependent
processes.
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mobility of AMPARs and enhancing AMPAR
function. Blocking Stargazin phosphorylation
or dephosphorylation blocks LTP and LTD, respectively
(25).
AMPARs exist as tetramers made up of different
combinations of the four subunits, GluA1
through 4. The cytoplasmic tails of each subunit
contain multiple phosphorylation sites that regulate
the trafficking of AMPARs. For example,
PKA phosphorylation of S845 in the long cytoplasmic
tail of GluA1 increases GluA1 surface
expression due to both enhanced insertion and
attenuated internalization (26). Conversely, LTD
of dissociated cultures and brain slices results in
dephosphorylation of S845 and is correlated with
an increased rate of AMPAR endocytosis (27).
Knock-in mice with phosphorylation-deficient
mutations at both S831A and S845A display a
loss of NMDA-induced AMPAR internalization,
deficits in LTP and LTD, and have impaired spatial
memory (28).
Although studies of posttranslational modifications
at individual sites have established a
role for regulating GluA1 trafficking and channel
properties, they do not fully account for the
changes in GluA1 function observed with synaptic
plasticity (29). Activity-modified residues
continue to be discovered, including, for example,
the highly conserved T840 phosphorylation
site, the phosphorylation of which correlates remarkably
well with synaptic strength (30). It is
likely that complex patterns of phosphorylation
and of other post-translational modifications (e.g.,
palmitoylation or ubiquitination) combine to regulate
AMPAR localization.
Trans-Synaptic Signaling; the Synaptic Cleft
The synaptic cleft is a ~20-nm junction between
the pre- and postsynaptic compartments, consisting
of a space through which neurotransmitters
diffuse to bind postsynaptic receptors, as well as
a network of cell adhesion molecules (CAMs)
that keeps the synapse together. These adhesive
interactions are so strong that it is impossible to
separate intact pre- from postsynaptic compartments
biochemically.
Role of CAMs in synaptic plasticity. The CAMs
that localize to the synaptic cleft include members
of the cadherin, integrin, and immunoglobulincontaining
CAMs, as well as neurexins and neuroligins.
Much research has focused on trying to
understand whether and how CAMs mediate
synapse specificity during neural circuit formation.
Here we focus on the regulation of synaptic
CAMs during experience-dependent synaptic
plasticity, limiting our discussion to just two of
many examples.
One such example involves the addition of
large sialic acid homopolymers to the neural
cell adhesion molecule (NCAM) to form polysialylated
NCAM (PSA-NCAM), which decreases
homophilic adhesion to allow new synaptic remodeling
and growth. The ratio of PSA-NCAM
1
2
3
5
Transcription
Export
RNA
granule
RNA trafficking Synapse to nucleus signalsSplicing and processing
RBPs
RBPs
AAAAAAAAAA
PABP
elF4E
4EBP
m7
G
40S
Local
translation
Proteasome
Local
degradation
Nascent
polypeptide
AAAAAAAAAA
PABP
elF4E
40SelF4G
m7
G
elF2
GTP
Met-i
4
AAAAAAAAAA
m7
G
60S
eEF2
40S
Folded protein
Ubiquitin
Degraded
protein
Ub Ub Ub Ub
Fig. 4. Local regulation of the synaptic proteome. Synaptic plasticity modifies
gene expression at many levels. Strong stimulation of synapses triggers signals
that are sent to the nucleus to modify RNA synthesis. Synaptic activity also
modifies protein synthesis, and has been found to act at several key steps
during translation: (1) Relief of repression, e.g., RISC-mediated repression; (2)
modification of translational initiation to allow 4E-4G interaction and recruitment
of 40S; (3) formation of the preinitiation complex; and (4) dephosphorylation
of eEF2 to allow for catalysis of ribosome translocation
during translational elongation. To counterbalance local protein synthesis,
local protein degradation also occurs at synapses (5). Together, these regulated
steps in protein addition and removal allow for rapid, spatially restricted
control of the synaptic proteome. Lightning bolts indicate activity-dependent
processes. RBP, RNA binding proteins such as exon junction complexes, RISC
machinery, Staufen, CPEB, etc. (Note: Although local translation in dendrites is
a well-accepted phenomenon, it has not been demonstrated to occur in
spines.)
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to NCAM increases following hippocampal
learning tasks, and inactivation of the enzyme
that adds the polysialic moieties blocks hippocampal
learning and plasticity (31). The increase
in PSA-NCAM is thought to promote
synaptic remodeling during persistent forms of
plasticity.
Another family of CAMs that play a role in
hippocampal plasticity includes the synaptically
localized receptor tyrosine kinase ephrins and
ephrin receptors (Eph receptors). Initially studied
in the context of neural development, ephrins and
Eph receptors have also been found to be essential
for hippocampal LTP and LTD in the adult
brain (32). Specific ephrins and Eph receptors
regulate the localization and function of NMDA
receptors, and can thereby modulate synaptic
strength in response to activity. Experiments
using inhibitory ephrin and Eph receptor peptides
have revealed that both molecules are required,
in a kinase-independent manner, for mossy fiber
hippocampal LTP (33).
Trans-synaptic signaling by retrograde messengers.
Another means of trans-synaptic signaling
involves diffusible, membrane-soluble messengers.
The CB1 and CB2 cannabinoid receptors
were initially identified as receptors for cannabinoid,
the active ingredient of THC/marijuana.
This led to the identification of endogenous CB1
and CB2 ligands, called endocannabinoids. Endocannabinoids
have emerged as important modulators
of plasticity, initially at inhibitory synapses,
and more recently at excitatory synapses (34). Depolarization
and activation of a variety of receptors
have been shown to activate release of endocannabinoids
from the postsynaptic compartment
and binding to presynaptic CB receptors, resulting
in a suppression of neurotransmitter release
(and thus regulating presynaptic plasticity). This
form of plasticity is called endocannabinoid-LTD,
or eCB-LTD. Endocannabinoid signaling is required
for extinction but not acquisition of spatial
memories (35).
The Tripartite Synapse: Glia and
Synaptic Plasticity
Once thought of as the “support cells” of the
nervous systems, glial cells are now considered
essential partners in synapse formation, synaptic
transmission, and plasticity (36). Astrocytes surround
the synapse (Fig. 2), forming a “tripartite
synapse,” composed of neuronal pre- and postsynaptic
compartments as well as surrounding
astrocytes. Synaptically localized glia release neuroactive
molecules that influence neuronal communication.
For example, release of D-serine (a
coactivator of the NMDA receptor) from glia is
required for LTP of hippocampal Schaffer collateral
synapses (37) [although see also (38)].
Ephrin and Eph receptor signaling between neurons
and glia regulates the uptake of glutamate
through glial glutamate transporters and thereby
affects neurotransmission and synaptic plasticity
(39). The release of lactate from astrocytes
and uptake by neurons has also been reported
to be required for long-term hippocampal memory
and plasticity (40).
Regulating Gene Expression Within
Neurons During Plasticity
Signaling from synapse to nucleus to regulate
transcription. Long-lasting forms of synaptic plasticity,
such as those underlying long-term memory,
require new RNA synthesis (2). This indicates
that synaptic signals must be relayed to the nucleus
to regulate transcription. Synapse-to-nucleus
signaling poses a unique set of challenges in
neurons, where the distance between the synapse
and nucleus can be appreciable. Neurons
are specialized for rapid communication between
compartments via electrochemical signaling, with
depolarization at the synaptic terminal leading
to depolarization at the soma in less than a
millisecond. Calcium influx can occur through
voltage- and ligand-gated ion channels. Cytosolic
calcium can also be released from intracellular
pools following activation of Gq-coupled receptors
such as metabotropic GluRs (mGluRs). Each
route of calcium influx induces different programs
of gene induction (41).
Soluble signals can also be transported from
the synapse to the nucleus by slower, microtubuleand
motor protein–dependent pathways (42). This
class of signals includes kinases and transcriptional
regulators that function to alter transcription.
These slower pathways of signaling to the
nucleus may sustain changes in gene expression
for time periods extending beyond the initial
stimulus.
To obtain a global view of how transcription
is altered during activity-dependent plasticity,
expression profiling has been used to identify
changes in transcription following depolarization
of cultured mouse neurons. Such studies
have identified several hundred activity-regulated
genes (41). Genome-wide analyses of transcription
factor binding sites of the activated genes
have revealed that the transcription factors CREB,
MEF2, and Npas4 control the activity-dependent
transcription of a large number of downstream
activity-regulated genes (41). These downstream
transcription factors regulate the expression of
overlapping but distinct subsets of activity-regulated
genes, suggesting that the precise temporal, spatial,
and stimulus-specific cellular response is
achieved by the combinatorial control by different
transcription factors.
Local protein synthesis. Despite requiring
new transcription, LTP and LTD can occur in a
spatially restricted manner, raising the question
of how gene expression in neurons can be limited
to subsets of synapses and not generalized
to the entire cell. One way of locally changing
the proteome in neurons is through regulated
translation of localized mRNAs (Fig. 4).
The existence of local translation in dendrites
of mature neurons was first suggested by electron
micrographic identification of polyribosomes
in hippocampal dendrites (43). Studies in hippocampal
slices in which dendrites had been severed
from cell bodies found that such dendrites
retain the ability to express long-lasting LTP and
LTD, indicating that local translation can mediate
long-term modification of synaptic strength
(44, 45).
Studies of mRNA localization have led to
the identification of cis-acting RNA elements
that bind to RNA-binding proteins to undergo
export from the soma into the dendrite (46). Although
several dendritic localization elements
have been identified, there is to date no consensus
on their sequence or structure. Among the beststudied
RNA binding proteins involved in dendritic
mRNA localization are Staufen, Zipcode
binding protein 1 (ZBP1), and hnRNPA2 (46).
These proteins bind cis-acting elements and assemble
transcripts into larger RNA transport
granules, which travel in a kinesin-dependent
manner along microtubules to their final destination.
Whether localized RNAs undergo directed
targeting, anchoring, or stabilization at specific
sites remains an open question.
In terms of translational regulation, studies
have revealed activity-dependent regulation of
translation initiation and elongation. A mechanism
of translational regulation known to occur
at synapses involves the cytoplasmic polyadenylation
element binding protein (CPEB). CPEB
binding to 3′ untranslated regions (3′UTRs) represses
translation. However, CPEB undergoes
phosphorylation in an activity-dependent manner
to recruit other proteins that increase the
polyadenylate [poly(A)] tails of mRNAs. Subsequently,
poly(A) binding protein (PABP) is
recruited to the elongated poly(A) tail, which in
turn recruits eukaryotic translation initiation factor
4g (eIF4G) to interact with eukaryotic translation
initiation factor 4E (eIF4E) to promote
translation initiation (47). CPEB localizes to
synapses, where it regulates translation of dendritically
localized CamKIIa mRNA (48, 49).
Another activity-dependent means of regulating
translation initiation involves phosphorylation
of eIF4E-binding proteins (4E-BPs).
Hypophosphorylated 4E-BPs bind eIF4E and
prevent translation initiation; phosphorylated
4E-BP dissociates from eIF4E and relieves translational
inhibition. In neurons, activity increases
4E-BP phosphorylation and stimulates translation
(50). Studies in 4E-BP2 knockout mice found
that E-LTP stimulation protocols could induce
L-LTP in brain slices. Recently, two additional
4E-BPs have been identified in neurons: neuroguidin
and the cytoplasmic FMRP interacting
protein (CYFIP). Whereas 4E-BP1 and 2 are believed
to affect general translation, these new
4E-BPs may preferentially affect subgroups of
transcripts within dendrites (51, 52).
Activity can also regulate translational elongation
during synaptic plasticity. For example, the
elongation factor eukaryotic translation elongation
factor 2 (eEF2) undergoes activity-dependent
changes in phosphorylation. Phosphorylation of
eEF2 decreases the rate of translation. Whereas
action potentials decrease eEF2 phosphorylation
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(thereby increasing translation), spontaneous release
of neurotransmitter increases eEF2 phosphorylation
and decreases translation (53). These
effects occur locally at synapses, indicating that
one function of spontaneous release may be to
suppress local translation and thereby stabilize
synapses.
Translation may also be regulated through
the microRNA (miRNA) pathway, where each
miRNA can potentially regulate hundreds of
transcripts and hence coordinate the expression
of many genes. Many miRNAs are relatively
more abundant in, or restricted to, the brain.
While miRNAs can regulate cell-wide levels of
translation, their posttranscriptional mode of
action makes them especially well suited to regulating
distally localized transcripts. Specific
miRNAs have been found in dendrites and synapses,
and components of the RNA-induced silencing
complex (RISC) machinery itself have
been found to be altered by activity (54).
Consistent with the importance of regulating
synaptic AMPAR concentrations during plasticity,
the mRNAs encoding GluA1 and GluA2 have
both been detected in hippocampal dendrites
and found to undergo activity-dependent changes
in localization and translation (55, 56). Further
linking local translation with synaptic AMPAR
abundance, local eEF2-dependent translation
of Arc mRNA has been shown to trigger endocytosis
of AMPARs during mGluR-mediated
hippocampal LTD (57, 58).
Local protein degradation. The local proteome
is regulated not only by local translation
but also by protein degradation through the
ubiquitin proteasome system (Fig. 4). Both
protein synthesis and degradation are required
for the maintenance of late-phase LTP, suggesting
that protein degradation is needed to counterbalance
protein synthesis during plasticity (59).
Like local translation, protein degradation can
be regulated within dendrites. Ubiquitin and proteasomal
subunits have been found in dendrites
and at synapses, and stimulation of hippocampal
neurons triggers proteasome-dependent changes
in the composition of PSD proteins (60). Activitydependent
degradation involves redistribution
of proteasomes from dendritic shafts to spines
(61). Notably, the ubiquitin proteasome pathway
alters AMPAR trafficking and degradation at
synapses during plasticity (62).
Perspectives
As the above examples illustrate, cell biological
approaches have provided a detailed understanding
of many aspects of activity-dependent
plasticity. By focusing on molecular processes
occurring within individual neurons and subcellular
compartments, we now understand specific
processes that are modulated by experience
to change synaptic strength. These involve alterations
in neurotransmitter release, trans-synaptic
signaling, postsynaptic receptor dynamics, and
gene expression within neurons. Distinct plasticity
mechanisms are used at different types of synapses.
For instance, LTP at mossy fiber synapses
occurs primarily through presynaptic changes,
whereas LTP at Schaffer collateral synapses occurs
mostly through postsynaptic mechanisms.
The end result of many of the processes we have
described is to regulate the concentration of glutamate
receptors, indicating that this is a major
postsynaptic determinant of synaptic strength during
plasticity.
Together, each of these cell biological mechanisms
provides potential therapeutic targets
for diseases in which brain plasticity is dysfunctional.
However, they fall short of elucidating
how complex circuits are altered by experience
to store information and alter behavior. This will
require the development of tools for investigating
both the dynamic nano-architecture of the synapse
and the neural circuit as a whole. A particular
challenge is to study plasticity in neural
circuits in living animals, and to develop methods
to examine, and computational frameworks to
understand, how all components of a circuit are
regulated to alter circuit function dynamically.
The development of methodologies for superresolution
time-lapse imaging of synapses, neurons,
and circuits in live animals promises to
move the field forward toward a more nuanced
and complete understanding of the experiencedependent
plastic changes in the brain that mediate
learning and memory.
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Acknowledgments: We apologize to those whose
primary work could not be cited because of space
constraints. We thank J.T. Braslow, T. J. O’Dell,
and F. E. Schweizer for comments on the manuscript;
J. Bourne and K. M. Harris for hippocampal
electron microscopy images; and all members
of the Martin lab for helpful discussions. Support
comes from NIH grants R01 MH077022 and R01
NS045324 (to K.C.M.), the Medical Scientist
Training Program (NIH T32 GM008042), and the
Neurobehavioral Genetics Training Program (NIH
grant T32 MH073526) (to V.M.H.). A glossary of terms
used is included in the online (HTML) version of this
article (Box 1).
10.1126/science.1209236
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