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10.1146/annurev.neuro.26.043002.094940
Annu. Rev. Neurosci. 2003. 26:485–508
doi: 10.1146/annurev.neuro.26.043002.094940
c 2003 by Annual Reviews. All rights reserved
Copyright °
First published online as a Review in Advance on February 26, 2003
CELL-CELL SIGNALING DURING SYNAPSE
FORMATION IN THE CNS
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Peter Scheiffele
Columbia University, Department of Physiology and Cellular Biophysics, and Center for
Neurobiology and Behavior, College of Physicians and Surgeons, P&S 11-511, 630 West
168th Street, New York, NY 10032; email: ps2018@columbia.edu
Key Words development, axon, dendrite, target recognition, active zone
■ Abstract Synapses join individual nerve cells into a functional network. Specific
cell-cell signaling events regulate synapse formation during development and thereby
generate a highly reproducible connectivity pattern. The accuracy of this process is
fundamental for normal brain function, and aberrant connectivity leads to nervous
system disorders. However, despite the overall precision with which neuronal circuits
are formed, individual synapses and synaptic networks are also plastic and can readily
adapt to external stimuli or perturbations. In recent studies, several trans-synaptic
signaling systems have been identified that can mediate various aspects of synaptic
differentiation in the central nervous system. It appears that these individual pathways
functionally cooperate, thereby generating robustness and flexibility, which ensure
normal nervous system function.
INTRODUCTION
Neurons in the mammalian brain are joined into functional networks by trillions
of synaptic connections. The number, location, and function of these connections are remarkably well controlled, and synaptic circuits are formed in a very
reproducible way. This implies that specific cellular properties must exist that
determine the identity and connectivity of each neuron in the brain. This review
discusses the extracellular and transmembrane signaling molecules that contribute
to synapse formation. It is focused on the early events in the assembly of excitatory synapses during development of the vertebrate central nervous system
(CNS). Other important processes that contribute to the modification and function
of synaptic circuits, such as synapse elimination, synaptic plasticity, and synaptic
growth, are not covered but have been reviewed elsewhere (Lichtman & Colman
2000, Sheng & Kim 2002, Turrigiano & Nelson 2000). The understanding of
the molecular mechanisms contributing to synaptogenesis has been tremendously
facilitated by work on the neuromuscular synapse (NMJ) and synapse formation in invertebrates. Although some of this work is cited here in the context of
the principal mechanisms that may operate in the CNS, it is not discussed in
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detail. These subjects have been covered in recent review articles (Jin 2002, Sanes
& Lichtman 1999).
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General Principles of Synapse Formation
Central synapses are morphologically and functionally specialized junctions between two neurons that can communicate signals via neurotransmitters. Synaptic junctions are highly asymmetric with machinery for regulated secretion in
the presynaptic terminal and arrays of signaling molecules in the postsynaptic
membrane (Figure 1). Both membrane domains delineating the synaptic cleft are
coated with cytoplasmic scaffolds that can be visualized by electron microscopy
as electron-dense structures. Proteins that form these scaffolds have been identified, and several of them play important roles in the assembly and maturation of
synapses (Garner et al. 2000a,b; Sheng & Kim 2002). The synaptic cleft itself is
filled with proteinaceous and carbohydrate-containing material. Some of this material likely represents the extracellular domains of synaptic receptor-ligand protein
complexes that directly link presynaptic active zones and postsynaptic densities.
However, pre- and postsynaptic terminals are also connected at sites lateral to the
active zone that are called puncta adherentia. This latter type of cellular junction
is morphologically similar to tight junctions formed by epithelia, and several important molecular constituents of neuronal synapses are common to neurons and
Figure 1 Morphological characteristics of excitatory CNS synapses. Synaptic membranes are separated by the synaptic cleft, which is filled with fibrillar material consisting of proteins and carbohydrates. Presynaptic terminals contain mitochondria (M) and
accumulations of clear synaptic vesicles, some of which are docked at the active zone
that contains presynaptic cytomatrix components. Excitatory synapses often form on
postsynaptic spine structures, which contain large postsynaptic densities. Besides the
synaptic junction, pre- and postsynaptic terminals are also linked by puncta adherentia,
which flank active zones but also often localize to junctions on the dendritic trunks.
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MECHANISMS OF CNS SYNAPSE FORMATION
487
epithelial cells (Uchida et al. 1996). Some basic cell biological aspects of the assembly of junctional complexes may therefore be shared between these two cell
types. However, clearly, several functional and morphological features are unique
to synapses and require neuron-specific machinery.
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SYNAPSE FORMATION IS CONTROLLED
BY HIERARCHICAL SIGNALS
During development, specific synaptic circuits are generated by synapse formation
between the appropriate pre- and postsynaptic partners. When postsynaptic target
cells are eliminated by experimental manipulation there are two possible consequences. In some cases afferents will degenerate, indicating a requirement for
target-derived survival signals (Hamburger & Levi-Montalcini 1949). However,
in other cases, neuronal circuits can be remodeled and axons will form ectopic
synapses on cells that under normal circumstances never serve as targets (reviewed
in Sotelo 1982 and Vaughn 1989). The latter observation is paralleled by the finding that in vitro almost every vertebrate neuron will form functional synapses with
any other neuronal cell type, regardless of whether these cells would normally
form synapses in vivo. This finding indicates that the cell-cell interactions that
mediate synapse formation show a significant level of promiscuity, most likely
owing to the presence of basic machinery for synapse formation that is shared
by all neuronal cells. Furthermore, this implies that synaptic specificity is not
controlled by an absolute recognition event or by a “one synapse–one molecule”
mechanism but rather by a hierarchical set of signals. According to such a model,
pre- and postsynaptic cells would read a combination of synapse-promoting and
inhibitory signals and form synapses with the best available cell. Such signals
might operate on at least three different levels (Figure 2). The first is the control of
axon-target interactions: Contacts between synaptic partners are established depending on a balance of repulsive and attractive cues. Secondly, incipient synaptic
connections are formed through interactions between pre- and postsynaptic cell
surface molecules. Importantly, these incipient connections set the stage for the
subsequent signaling events and the activity-dependent processes that are required
to refine the initial network. This refinement represents the third phase in the
generation of synaptic circuits, where the more competitive connections are stabilized, whereas others are eliminated (Goodman & Shatz 1993, Katz & Shatz
1996).
CONTROL OF AXON-TARGET INTERACTIONS
Various guidance factors have been characterized that control the projection of
axons to their target areas (Tessier-Lavigne & Goodman 1996). However, within
the target area, growth cones still need to recognize the appropriate target cells
for synapse formation. This problem is well illustrated in the developing mouse
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Figure 2 Model for the stepwise assembly of CNS synapses. (A) Axonal growth
cones read a combination of attractive (+) and repulsive (−) target-derived cues. All
neuronal cells (a–c) appear to contain significant levels of synapse-promoting factors,
but in some cells (a) abundant repulsive factors minimize the extent of axon-target interactions. Candidate target-derived signals are Semaphorins, WNT-family molecules,
and polysialic acid. However, growth cone dynamics and thereby cell-cell interactions
can also be regulated by the extracellular glutamate concentration ([Glu]). (B) Upon
contact, signaling through homophilic and heterophilic receptors induces the formation of incipient connections. The assembly of scaffolds in the pre- and postsynaptic
terminal leads to recruitment of additional signaling molecules. (C ) Connections with
productive signaling will be stabilized, whereas incipient connections that lack compatible trans-synaptic signaling systems will be eliminated.
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MECHANISMS OF CNS SYNAPSE FORMATION
489
cerebellum, where mossy fiber afferents need to “choose” between Purkinje and
granule cells as potential synaptic partners, even after they have been guided into
the appropriate lobules of the cerebellar cortex (Mason et al. 1997). Initial contacts
between synaptic partners are frequently established by filopodia extending from
axons and dendrites (Jontes & Smith 2000, Ziv & Smith 1996). Consequently,
secreted factors that regulate filopodial dynamics should play important roles in
regulating axon-target interactions. Preventing physical contact between inappropriate partners by repulsive signals or encouraging interactions with the appropriate
target cells should provide a mechanism that promotes specific synapse formation
at a very early stage. Several factors that may be involved in this process have been
identified and are discussed below.
Semaphorins
Semaphorins (Semas) are a family of at least 20 secreted and membrane-bound
proteins (Semaphorin Nomencl. Comm. 1999). The first family members were
originally discovered as repulsive axon guidance factors, which can induce growth
cone collapse by signaling to the actin cytoskeleton (Kolodkin et al. 1993, Luo
et al. 1993). Subsequent experiments suggested that Semas could also function
in target selection and synapse formation in invertebrates. Loss of Sema II expression in Drosophila led to promiscuous synapse formation with inappropriate
target muscles (Matthes et al. 1995, Winberg et al. 1998), and Sema Ia mutants
revealed a function for this transmembrane Semaphorin in bidirectional signaling
at central synapses (Godenschwege et al. 2002). In both cases Semaphorins act
as inhibitory factors for synapse formation. A function of Semaphorins in synaptogenesis in the vertebrate CNS has not been analyzed in detail. However, it has
been suggested that Sema III might have a similar function in the inhibition of
promiscuous synapse formation by ponto-cerebellar mossy fibers. Mossy fibers
enter the cerebellar cortex around E18 and extend toward the Purkinje cell layer
(Mason et al. 1997). At this developmental time point, only a small number of
the appropriate target cells—mature Golgi and granule cells—are present in the
cerebellar cortex. However, aberrant synaptic connections between mossy fibers
and Purkinje cells are formed only very rarely (Mason & Gregory 1984). Purkinje
cells express Sema III, a secreted Semaphorin that induces collapse of mossy fiber
growth cones in vitro (Rabacchi et al. 1999). These findings suggest that Sema III
may act as an inhibitory factor, similar to Sema II at the Drosophila neuromuscular junction, which prevents promiscuous synapse formation. However, analysis of
Sema III mutant mice did not reveal increased aberrant synapse formation between
pontine mossy fibers and Purkinje cells (Catalano et al. 1998), possibly because of
functional redundancy with other Semaphorins expressed in Purkinje cells, such
as Sema K1 (Xu et al. 1998). Consequently, direct evidence for an in vivo function
of Semaphorins in synapse formation in the vertebrate CNS is still missing; however, they are good candidates to be negative regulators of axon-target interactions
during development.
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WNTs
Whereas secreted Semaphorins destabilize the cytoskeleton in axonal growth cones
to inhibit inappropriate synapse formation, WNT factors may induce growth cone
remodeling that would promote synaptic differentiation. WNTs are secreted signaling molecules that bind to the seven-pass transmembrane receptor Frizzled. WNT
signaling can affect gene expression via nuclear translocation of beta-catenin and
activation of T-cell factor (LEF/TCF)-mediated transcription but can also have
more direct effects on the cytoskeletal organization (Moon et al. 2002). Granule
cells in the mouse cerebellum express WNT-7a during early postnatal development. Exposure of cultured cerebellar granule cells or pontine mossy fibers to
WNT-7a induces spreading of the axonal growth cones (Lucas & Salinas 1997).
Consistent with a role for WNT-7a in synaptic differentiation of cerebellar granule
cells and/or mossy fibers, homozygous WNT-7a mutant mice show a transient
delay in the formation of mossy fiber rosettes at P8 and P10. The morphological
effects of WNT-7a on growth cones in vitro can be mimicked by pharmacological
inhibition of the signaling protein glycogen synthase kinase-3 (GSK-3), which
suggests that WNT-7a acts by inactivating GSK-3 (Hall et al. 2000).
GSK-3 also appears to be a downstream target for Semaphorin signaling. Exposure of dorsal root ganglion neurons to Sema III activates an inactive pool of GSK-3
at the leading edge of the growth cone (Eickholt et al. 2002). Sema III and WNT-7a
may therefore provide competing inputs that regulate GSK-3 activity. GSK-3 might
ultimately control the phosphorylation state of the microtubule-associated protein
MAP-1B and thereby the stability of microtubules in the growth cone (Lucas et al.
1998). A related MAP-1B-like molecule in Drosophila has also been described to
be involved in the growth of synaptic boutons at the NMJ (Hummel et al. 2000,
Roos et al. 2000), which further supports the notion that microtubule stability plays
an important role in the assembly of presynaptic terminals. However, GSK-3 may
also directly regulate the actin cytoskeleton through other effectors (Eickholt et al.
2002).
Regulation of Cytoskeletal Dynamics by Neurotransmitters
There is clear evidence that synaptic activity controls the refinement of synaptic
circuits (Goodman & Shatz 1993, Katz & Shatz 1996). More recent studies revealed that signaling induced by the neurotransmitter glutamate can also directly
modify cytoskeletal dynamics at earlier stages of development. First evidence
supporting this notion came from the observation that NMDA receptor–dependent
long-term potentiation (LTP) induction led to the formation of dendritic protrusions
in hippocampal neurons (Engert & Bonhoeffer 1999, Maletic-Savatic et al. 1999).
Subsequent experiments demonstrated that activation of postsynaptic AMPA receptors by glutamate application inhibited actin-based spine motility (Fischer et al.
2000). Although these effects relate to actin dynamics in neurons with established
synapses, glutamate was also shown to affect filopodial dynamics in neurons before
synapse formation. Activation of axonal AMPA and/or kainate receptors by local
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MECHANISMS OF CNS SYNAPSE FORMATION
491
glutamate application to isolated hippocampal neurons in culture strongly reduced
filopodia motility in axons (Chang & De Camilli 2001). As growing axons show
action potential propagation and neurotransmitter release, even before synaptic
connections are formed, glutamate released from vesicles in the axon may act in
an autocrine loop on glutamate receptors within the same cell. Axons could thereby
sense the concentration of extracellular glutamate. Upon contact with the target
cells the extracellular space for diffusion of glutamate would decrease, and, consequently, the effective local glutamate concentration would increase. As higher
glutamate levels reduce the filopodia dynamics, glutamate receptor signaling may
thereby stabilize newly formed connections with targets. Such a mechanism for the
regulation of the axonal and dendritic cytoskeleton could optimize the dynamics of
axon-target interactions during development; however, it appears not to be essential for the initial formation of neuronal circuits. Mouse mutants in which synaptic
vesicle release is blocked owing to deletion of munc-18, an essential component
of the transmitter release machinery, were reported to develop morphologically
normal synaptic circuits (Verhage et al. 2000). Neuronal activity and glutamate
release therefore appear to be able to modulate early steps in the development of
synaptic networks; however, they are only essential for the refinement of these
circuits at later stages.
Polysialic Acid
A general inhibitor of cell-cell interactions that affects axon-target interactions
during development is the carbohydrate polysialic acid (PSA). PSA is attached
to a specific isoform of the adhesion molecule NCAM (see below) but is also
found on other cell extracellular proteins. During the phases of axon outgrowth
and synaptogenesis, PSA levels are high and decline later in development once an
initial synaptic network has been formed. Electron microscopic studies in mice
revealed that PSA is absent from the synaptic cleft (Bruses et al. 2002). In further
experiments where PSA levels were reduced by either genetic manipulation or
enzymatic digestion it was shown that removal of PSA induced ectopic synapse
formation in the hippocampal pyramidal layer (Seki & Rutishauser 1998). This
phenotype is most likely due to the failure to withdraw aberrant mossy fiber projections from this layer, indicating that the presence of PSA under normal conditions
serves as negative regulator of synapse formation and stabilization. Consistent with
this hypothesis, it has been demonstrated that PSA, when conjugated to a variety
of adhesion molecules, functions as a general inhibitor of adhesive interactions
(Fujimoto et al. 2001), presumably as a result of its general electrostatic properties
and its size, which can prevent interactions by sterical hindrance.
All the factors discussed above are good candidates to control initial axontarget interactions during the initiation of synapse formation. Most likely, growth
cones will be confronted to a combination of these various cues and respond to
the balance of their attractive and repulsive activities (Figure 2). Because most of
these factors have been shown to ultimately affect the cytoskeleton, their activities
are likely to be integrated at that level.
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TRANS-SYNAPTIC SIGNALING AND
ADHESION SYSTEMS
Once initial axon-target interactions develop, signaling molecules can engage in
bidirectional signaling to coordinate the differentiation of pre- and postsynaptic
membrane specializations. Several cell-surface receptor systems have been identified that might mediate this process through their adhesion and signaling capabilities. In fact, it is not possible to clearly divide them into adhesion and signaling
systems because classical adhesion molecules, such as cadherins, have signaling
functions (Gottardi & Gumbiner 2001), and signaling molecules, such as the Ephreceptor tyrosine kinases and their Ephrin ligands, have adhesive characteristics
(Bohme et al. 1996, Klein 2001).
Trans-synaptic signaling systems need to fulfill several functions during the
initial steps of synaptic differentiation:
1. Functional differentiation of the pre- and postsynaptic membrane needs to
be coordinated. Both membrane specializations need to be precisely juxtaposed to ensure efficient neurotransmission. Furthermore, the presynaptic neurotransmitter and the postsynaptic receptor type need to be matched
(e.g., glutamate-containing presynaptic vesicles and postsynaptic glutamate
receptors).
2. Synapses are highly asymmetric. Specific signals need to ensure directionality to generate the fundamentally different structures of pre- and postsynaptic
terminals.
3. Synaptic circuits connect select subsets of cells. Synaptic signaling needs to
mediate the selective formation or stabilization of the appropriate connections and destabilize inappropriate contacts.
We are still far from understanding the molecular mechanisms that underlie
most of these important aspects of synaptic differentiation in the CNS. However,
one principle that has emerged from recent studies is that homophilic interactions
are often employed to promote selective interactions between specific pre- and
postsynaptic partners. In these cases, matching sets of cadherins or Ig-domain
proteins are specifically expressed in afferents and targets and thereby mediate
selective adhesion that might promote the formation of the appropriate synaptic
connections (Benson et al. 2001, Shapiro & Colman 1999, Yamagata et al. 2002).
It is likely that such interactions synergize with a general synaptogenic machinery
that is common to all neuronal cells. This basic machinery should at least in part
employ heterophilic interactions to introduce directionality into the differentiation process. In the following section, some of the major trans-synaptic signaling
systems are discussed.
Neuroligins and Neurexins
Neuroligins and Neurexins are candidates to be part of the general machinery
that mediates synapse assembly during development. Both proteins are widely
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MECHANISMS OF CNS SYNAPSE FORMATION
493
expressed in the nervous system. The Neurexin family of transmembrane proteins
was first identified as receptors for alpha-latrotoxin, the venom of the black widow
spider, which triggers massive neurotransmitter release (Ushkaryov et al. 1992).
One fascinating aspect of the Neurexin family is the large number of isoforms. In
mice, three Neurexin genes are each transcribed from two alternative promoters
yielding six transcripts that are encoding the alpha- and beta-Neurexins. From these
transcripts, more than 1000 Neurexin isoforms are generated by alternative splicing, which are differentially expressed in the nervous system (Missler et al. 1998).
A subset of these isoforms, the beta-Neurexins, which lack a splice insertion in
splice site 4, binds to a second family of transmembrane proteins, termed Neuroligins (Ichtchenko et al. 1995, 1996). Three Neuroligin genes have been identified
in rodents and five in humans. Neuroligin-1 has been localized to the postsynaptic
membrane of excitatory synapses by electron microscopy, and Neuroligins and
beta-Neurexins can act as calcium-dependent heterophilic adhesion molecules in
cell aggregation assays, which suggests that they might mediate synaptic adhesion
(Nguyen & Südhof 1997, Song et al. 1999).
It still remains to be determined what role Neuroligins and Neurexins play
in vivo; however, in vitro experiments suggest a function for both molecules in
synapse formation. Overexpression of Neuroligin in dissociated cultures of cerebellar or hippocampal neurons leads to recruitment of Neurexins to cell-cell contact
sites and results in a fivefold increase in the number of synaptic puncta (C. Dean,
F.G. Scholl, J. Choih, S. DeMaria, J. Berger, E. Isacoff, and P. Scheiffele, submitted). Conversely, the formation of synaptic vesicle clusters in cerebellar cultures
can be reduced by addition of recombinant Neurexin in soluble form, presumably by blocking interactions between endogenous Neuroligins and Neurexins.
Neuroligin-Neurexin interactions may be sufficient to induce presynaptic differentiation because expression of Neuroligin-1 in nonneuronal cells can trigger the
assembly of functional presynaptic terminals in axons that contact these cells
(Scheiffele et al. 2000).
The molecular mechanism of Neuroligin-induced synapse formation still remains to be understood. Neuroligin and Neurexin both interact with cytoplasmic
scaffolding molecules that may be mediators of their synaptic functions. Neuroligin binds to PSD-95 (Irie et al. 1997), a major component of postsynaptic
densities, which can recruit a large number of additional PSD components (Sheng
& Kim 2002). PSD-95 has been shown to facilitate the assembly of multimeric
complexes of other cell-surface molecules and may similarly induce clustering
of Neuroligins in the postsynaptic membrane (Craven & Bredt 1998; El-Husseini
et al. 2000). Neuroligin activity depends on lateral clustering between individual
Neuroligin molecules (C. Dean, F.G. Scholl, J. Choih, S. DeMaria, J. Berger, E.
Isacoff, and P. Scheiffele, submitted). Such lateral complexes of Neuroligin might
induce clustering of Neurexin in the presynaptic membrane and thereby recruit
scaffolding molecules, such as CASK, Mint, and CIPP, that can interact directly
with the cytoplasmic tail of Neurexins (Biederer & Südhof 2000, Kurschner et al.
1998). CASK also interacts with protein band 4.1N, which stabilizes the actinspectrin submembrane cytoskeleton (Biederer & Südhof 2001). Into this initial
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presynaptic scaffold, additional Neurexin molecules and/or other synaptic factors
may be inserted, driving the expansion and stabilization of incipient contacts.
An attractive hypothesis is that Neuroligin-Neurexin interactions might induce
the recruitment of calcium channels to the forming presynaptic terminal. Synaptic
localization of the pore-forming alpha1 subunit of voltage-gated calcium channels (VGCCs) depends on interaction with the scaffolding molecule Mint1, which
might link Neurexin and the alpha1 channel subunit via two independent binding
sites (Maximov & Bezprozvanny 2002, Maximov et al. 1999). Consistent with a
rapid recruitment of VGCCs during synapse formation, depolarization-dependent
local calcium influx has been observed within minutes after contact of growth cones
with muscle target cells (Dai & Peng 1993, Zoran et al. 1993). Furthermore, in
hippocampal neurons the alpha1B subunit of N-type VGCCs is rapidly recruited in
response to contact with a postsynaptic neuron (Bahls et al. 1998). VGCCs can interact with various cytoplasmic active zone components. Furthermore, the accumulation of VGCCs would generate a hotspot for calcium-dependent exocytosis at the
newly forming terminal, which would promote local recycling of synaptic vesicles.
Eph Receptors and Ephrins
EphB-receptor tyrosine kinases and their membrane-bound EphrinB ligands represent a second class of heterophilic signaling molecules at the synapse. Eph receptors have been well characterized as repulsive axon guidance molecules during
earlier stages of nervous system development (Flanagan & Vanderhaeghen 1998).
Expression of EphB receptors is downregulated after E14, but expression levels
increase again around P6 when synapse formation occurs and remain high in the
adult (Henderson et al. 2001). Although receptors are found on axonal growth
cones during the phase of axon guidance, they are restricted to dendrites in postnatal development (Henderson et al. 2001). Electron microscopy analysis revealed
a postsynaptic localization of EphB2 and EphB3 in the CA1 region of the hippocampus of adult rats (Buchert et al. 1999). EphrinB ligands were proposed to be
present in the presynaptic terminals; however, so far their localization has not been
analyzed on the ultrastructural level (Contractor et al. 2002, Torres et al. 1998).
Several recent findings suggest an important postsynaptic function for EphB receptors. EphB2 can interact directly with the NMDA-receptor subunit NR1 via the
extracellular domain (Dalva et al. 2000). Clustering of EphB receptors with recombinant EphrinB-ligands strongly promotes this interaction in dissociated cortical
neurons and leads to the generation of NR1 clusters at the cell surface. Furthermore, stimulation of cortical neurons over several days with clustered EphrinBligands leads to a 1.5-fold increase in the number of pre- and postsynaptic sites
(Dalva et al. 2000). It is striking that EphB2 knockout mice show a 40% reduction in the number of NR1-containing receptors in asymmetric synapses, which
suggests that Ephrin-EphB2 interactions might regulate synaptic recruitment or
retention of NMDA receptors (Henderson et al. 2001). Consistent with a reduction
in the number of synaptically localized NR1 subunits, EphB2-deficient mice show
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MECHANISMS OF CNS SYNAPSE FORMATION
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reduced NMDA-mediated currents and reduced LTP at hippocampal CA1 and
dentate gyrus synapses. Furthermore, long-lasting LTP (L-LTP) and long-term
depression (LTD) were strongly impaired (Grunwald et al. 2001). LTP and LTD
were rescued in knock-in mice expressing a kinase-deficient EphB2 (Grunwald
et al. 2001, Henderson et al. 2001). Therefore, either the role of EphB2 in synaptic
plasticity is independent of the tyrosine kinase activity, or kinase-deficient EphB2
can coassemble with other EphB receptors expressed in the same cell, which may
replace the kinase activity.
Besides regulating the abundance of NMDA receptors at synapses, EphB2 activation might also directly regulate NMDA-receptor function. Stimulation of dissociated cortical neurons with recombinant B-Ephrins leads to tyrosine phosphorylation of the modulatory subunit NR2B by src-kinases (Grunwald et al. 2001, Takasu
et al. 2002). This phosphorylation event appears to increase the calcium permeability of the NMDA receptor such that glutamate stimulation of cells results in
increased calcium influx through the receptor and activation of CREB-dependent
transcription (Takasu et al. 2002). These findings established a role for EphB
receptors in postsynaptic signaling and function.
Previous observations demonstrated a retrograde signaling capability of BEphrins, the EphB-ligands in nonneuronal cells (Brückner et al. 1997, Holland
et al. 1996). Consequently, Ephrin-EphB signaling in neurons might therefore also
affect the presynaptic terminal. A recent study reported that application of soluble
recombinant EphB2 to hippocampal slice cultures increased basal transmission and
occluded the potentiation of mossy fibers presumably by acting directly on Ephrins
in the presynaptic terminal (Contractor et al. 2002). Mossy fiber LTP was blocked
by extracellular addition of recombinant B-Ephrins or by intracellular perfusion of
the postsynaptic cell with reagents that block interactions with the EphB-receptor
cytoplasmic domains. This suggests that clustering of postsynaptic EphB receptors
by cytoplasmic interactions might initiate a trans-synaptic signal by stimulating
presynaptic Ephrins. These findings expand the synaptic function of Ephrin-EphBsignaling to NMDA-receptor-independent forms of plasticity; however, it still remains to be shown whether Ephrins indeed localize to presynaptic terminals.
Although an involvement of Eph receptors in synaptic plasticity now appears
well established, it is unclear whether Ephrin-EphB-receptor signaling plays an essential role in the initial steps of synapse assembly. EphB2- and EphB3-deficient
mice form the same number of synapses as wild-type animals; however, other
Eph receptors or other functionally redundant factors might compensate for them
(Grunwald et al. 2001). In the hippocampus, EphB-receptor expression appears to
be very low in the first postnatal week, when many synapses are formed. However,
expression is upregulated in response to synaptic activity and rises rapidly in the
second postnatal week (Henderson et al. 2001). Low levels of dendritic EphB receptors might be sufficient to induce the assembly of postsynaptic, NR1-positive
structures, and transmission at these newly formed contacts might then stimulate EphB2 expression to further promote synapse formation. Alternatively, functional synapses may be established independently of EphB-receptor function, and
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subsequent expression and recruitment of the receptors might regulate maturation,
NMDA-receptor levels, and plasticity by trans-synaptic signaling.
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Ig-Domain Proteins
Several Ig-superfamily proteins have been implicated in synaptic interactions.
Members of this family contain in their extracellular sequences one or several
Ig-domains that consist of approximately 110 amino acids. Ig-domain proteins
frequently bind to multiple ligands by calcium-independent interactions. In some
but not all cases these interactions might mediate heterophilic or homophilic cell
adhesion.
NEURAL CELL ADHESION MOLECULE (NCAM) NCAM interacts with several ligands, but it also functions as homophilic cell-adhesion molecule. Earlier during
development the protein is modified with high levels of polysialic acid (PSA),
which reduces the adhesive interactions of NCAM. After birth this modification is
strongly reduced and the developmental regulation of PSA conjugation to NCAM
thereby leads to an increase of adhesiveness once most neuronal circuits have
formed. NCAM-deficient mice have several brain abnormalities. The hippocampal mossy fiber projection is misorganized and shows defects in lamination and
fasciculation (Cremer et al. 1997). Individual mossy fiber boutons, basal transmission, and short-term plasticity at mossy fiber synapses are normal, but LTP
is significantly reduced (Cremer et al. 1998). However, NCAM is largely absent
from mossy fiber terminals and is mostly detected at the axonal plasma membrane of fasciculating mossy fibers (Schuster et al. 2001). The reduction in LTP
is therefore not directly due to a function of NCAM as a synaptic cell-adhesion
molecule. NCAM may be required for the remodeling of the mossy fiber terminal
during LTP, but defects in the NCAM mutant mice may also reflect more general
developmental changes that might abolish the ability of hippocampal mossy fibers
to undergo presynaptic LTP. Therefore, although NCAM has important functions
during axon outgrowth and pathfinding in the nervous system, it is unlikely to
mediate critical trans-synaptic interactions that contribute to synapse formation
during development.
SYNAPTIC CELL ADHESION MOLECULE (SynCAM) SynCAM, a transmembrane protein containing three Ig-domains, was identified by database searches for transmembrane proteins containing extracellular Ig-domains and an intracellular Cterminal PDZ-binding motif (Biederer et al. 2002). The protein fulfills several criteria that suggest it could function in synaptic adhesion: (a) It localizes to synapses;
(b) it mediates homophilic adhesion in cell aggregation assays; (c) it interacts with
CASK, a synaptic scaffolding molecule. SynCAM overexpression in dissociated
hippocampal neurons raises the mini frequency 2.7-fold, which suggests it might
increase the number of synaptic terminals or enhance presynaptic release. Furthermore, overexpression of the cytoplasmic tail of SynCAM resulted in a decrease in
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MECHANISMS OF CNS SYNAPSE FORMATION
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the density of active terminals and slowed the rate of synaptic vesicle exocytosis,
presumably by sequestering cytoplasmic binding partners (Biederer et al. 2002).
However, many of the molecules that interact with the C-terminus of SynCAM
can interact with other synaptic factors, e.g., CASK also binds to Neurexins and
Syndecans (Hata et al. 1996, Hsueh et al. 1998). This effect may therefore only partially result from an inhibition of the interactions downstream of SynCAM rather
than a more general effect on other adhesion and signaling systems. Contact with
SynCAM-expressing nonneuronal cells can induce functional terminals in axons,
as with Neuroligin-expressing cells. Furthermore, coexpression of the AMPAtype glutamate receptor subunit GluR2 together with SynCAM yields productive
glutamatergic transmission of these presynaptic terminals into a nonneuronal cell
(Biederer et al. 2002), demonstrating that the presynaptic terminal is fully competent to release neurotransmitter in a quantal form.
SynCAM and the Neurexin-Neuroligin system show overlapping expression
patterns in the CNS and may have partially redundant functions in the induction
of presynaptic differentiation. Whether either of these adhesion systems can also
organize postsynaptic structures is not known. Because Neuroligin-Neurexin interactions are heterophilic they might precede the SynCAM interactions during the
formation of synapses. Neurexin and SynCAM can both interact with CASK as
a common cytoplasmic adapter protein. Incipient adhesion complexes containing
Neurexins might therefore recruit SynCAM through a common scaffold (or the
opposite).
SIDEKICKS Sidekick-1 and -2 are two homophilic adhesion molecules that were
identified in a screen for genes that are differentially expressed in subsets of neurons
in the retina (Yamagata et al. 2002). The proteins are 59% identical on the amino
acid level and have a similar domain structure consisting of 6 Ig-domains, 13
fibronectin type III repeats, a single transmembrane domain, and a C-terminal
PDZ-binding motif. Despite these similarities, each Sidekick protein appears to
form separate homophilic but not heterophilic complexes. Immunohistochemical
analysis demonstrated that Sidekick-1 and -2 are expressed in different subsets of
neurons in the retina where they are strongly concentrated at synapses. It is striking
that both proteins preferentially localize to specific sub-laminae. Misexpression of
Sidekick-1 or -2 in Sidekick-negative cells leads to aberrant termination of axons in
the Sidekick-positive laminae, suggesting that these proteins might control laminaselective synapse formation in the retina (Yamagata et al. 2002). Whether these
proteins also contribute to selective synapse formation between other populations
of neurons remains to be shown.
NECTINS Nectin-1, -2, -3, and -4 constitute a family of adhesion molecules with
three extracellular Ig-domains. Nectins are not neuron-specific but are found at
various types of cellular junctions. They were isolated in a screen for proteins interacting with afadin, a cytoplasmic scaffolding molecule, which contains a PDZ
domain, several proline-rich domains, and an F-actin binding site (Mandai et al.
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1997). The linkage of nectins to afadin is required for their localization to cell-cell
contact sites, and coupling of afadin to the actin cytoskeleton strongly increases the
adhesive interactions mediated through nectins (Miyahara et al. 2000). Cis-dimers
of nectins mediate homophilic adhesion with nectins in the opposing membranes
(in trans). Furthermore, nectin-3 can form heterophilic complexes with nectin-1
and -2 (Satoh-Horikawa et al. 2000). Similar to classical cadherins (see below),
nectins do not localize to the active zone of mature synapses but rather to puncta
adherentia (see Figure 1) (Mizoguchi et al. 2002). This suggests that they are part
of a different adhesion system than the one connecting presynaptic release sites
and postsynaptic densities. However, early in development of the hippocampal
mossy fiber synapses, nectins and afadin localize initially to the central domain
of immature synaptic contacts. Coinciding with the maturation of these incipient
contacts, components of the puncta adherentia and central synaptic domain are
progressively separated into different structures (Mizoguchi et al. 2002). Adherens
junctions are positioned at cell-cell contacts flanking the active zone, frequently
between the presynaptic terminal and the dendritic trunks, whereas the central domain containing the presynaptic release sites localizes opposite the postsynaptic
density in dendritic spines (Figure 1). This suggests that the adhesive interactions
mediated by components of the puncta adherentia might contribute to some aspects
of the initial assembly of cell-cell contacts or recognition between synaptic partners. A similar rearrangement of cell-cell adhesion molecules has been observed
during the formation of the immunological synapse where specific long-range
receptor-ligand pairs initiate contact between T cells and antigen-presenting cells,
which subsequently are displaced by other signaling complexes that will constitute
the central domain of the mature synaptic contact (Dustin & Colman 2002).
Cadherins
Cadherins mediate the formation of junctional complexes in a wide variety of cells
including epithelia, glia, and neurons (Takeichi 1988). Initially, a group of about 30
“classical” cadherins had been identified, which are expressed in various tissues.
Subsequently, additional members of the cadherin family were discovered that
are termed protocadherins (Kohmura et al. 1998, Sano et al. 1993). A remarkable
feature of this family is its molecular diversity, which might bring the total number
of cadherins expressed in the CNS to more than 100 proteins with different adhesive
and/or signaling properties (Wu & Maniatis 1999). Some cadherins are expressed
in cell pairs of pre- and postsynaptic partners that form functional synaptic circuits
during development (Fannon & Colman 1996, Obst-Pernberg & Redies 1999).
This observation is very intriguing because cadherins in nonneuronal cells can
mediate the sorting of cells into pools expressing the same cadherin family member
(Tepass et al. 2002). In the nervous system, matching cadherins in axons and
dendrites might therefore mediate a similar sorting event on the subcellular level
that promotes selective adhesion between axons and dendrites of the appropriate
partners.
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MECHANISMS OF CNS SYNAPSE FORMATION
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CLASSICAL CADHERINS The founding members of the cadherin family consist of
an extracellular domain containing five so-called EC domains of 110 amino acids.
Like nectins, classical cadherins do not localize to active zones but to adherens
junctions bordering or interspersed with the synaptic release sites (Uchida et al.
1996, Fannon & Colman 1996) (see Figure 1). They are therefore less likely to
be directly involved in the assembly and regulation of the neurotransmitter release
machinery itself. However, current evidence suggests that classical cadherins have
important functions in the structural assembly and reorganization of synaptic terminals, as well as for the selectivity of synapse formation during development.
Crystallographic and biochemical studies have provided a very detailed view
on the interactions underlying homophilic cadherin adhesion (Shapiro et al. 1995,
Tanaka et al. 2000). The N-terminal EC domain (EC1, distal from the membrane)
forms a dimerization interface with the EC1 domain of a cadherin in the opposite
membrane (in trans). Additional interactions are essential for strong cadherinmediated adhesion: (a) rigidification of the extracellular domain by calcium binding to residues between individual cadherin domains; (b) lateral clustering of cadherin molecules within the same membrane (in cis) via the cadherin ectodomain
(formation of cadherin strand-dimers); and (c) intracellular interactions with alphaand beta-catenins, which couple cadherins to the cytoskeleton. Consequently, adhesion through cadherins can be modified by regulation of these interactions. This
is particularly important because it allows for a dynamic regulation of cadherinmediated adhesion during development and synaptic plasticity.
Although it is still unclear how cadherins contribute to the initial assembly of
synapses, there are several findings that support a role for classical cadherins in
synaptic plasticity. In hippocampal slice cultures, LTP at Schaffer collateral–CA1
synapses is reduced by addition of antibodies directed against the extracellular
domain of N- or E-cadherin (Tang et al. 1998). Another study reported a selective
reduction of L-LTP after addition of antibodies that block N-cadherin-mediated
cell adhesion (Bozdagi et al. 2000). The same study confirmed that L-LTP is accompanied by an increase in the number of synaptic puncta and requires new protein
synthesis. Although the addition of anti-N-cadherin antibodies blocked L-LTP, it
did not block the increase in the number of synaptic puncta. This suggests that
new synaptic puncta assemble independently of N-cadherin, whether by de novo
formation of synapses, splitting of existing synapses, or by the stabilization and enlargement of synapses that could not initially be detected. N-cadherin might be required to stabilize or modulate morphological changes in the pre- and postsynaptic
cell. In fact, a recent study revealed a function of N-cadherin in spine morphogenesis (Togashi et al. 2002). Cultured hippocampal neurons expressing a dominantnegative cadherin mutant (which is lacking the ectodomain) showed spines of
irregular shape, often with filopodia-like morphology. Furthermore, the synaptic
vesicle marker synapsin and the postsynaptic scaffolding molecule PSD-95 were
less concentrated at synapses formed in cells expressing this dominant-negative
mutant. Similar but less dramatic phenotypes were observed in hippocampal cultures prepared from mice lacking alpha N-catenin, one of the cytoplasmic binding
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partners for cadherins (Togashi et al. 2002). Spines were elongated and irregular;
however, synaptic vesicle markers and the postsynaptic marker PSD-95 appeared
to be concentrated at synapses to the same extent as in cultures obtained from
alpha N-catenin-expressing neurons. In the cultures of alpha N-catenin-deficient
neurons N-cadherin and beta-catenin still localized to synapses, which indicates
that other alpha catenins, such as alpha E- or alpha T-cadherin, might partially
compensate for the loss of the protein.
The role of classical cadherins in LTP suggests that cadherin-mediated adhesion
might be modulated in response to cellular stimulation. Several recent studies support this hypothesis. Experiments in dissociated cultures of hippocampal neurons
revealed that N-cadherin transiently disperses in response to massive presynaptic
stimulation. Postsynaptic stimulation of NMDA receptors by direct application of
glutamate, on the other hand, induced the formation of cadherin strand-dimers, a
form that mediates increased adhesive interactions (Tanaka et al. 2000). In another
study it was observed that EGFP-tagged, overexpressed beta-catenin is recruited
from dendritic shafts into spines in response to depolarization of hippocampal
neurons (Murase et al. 2002). Recruitment of beta-catenin is likely to strengthen
cadherin adhesiveness at the synapse and might in fact be responsible for the
formation of cadherin strand-dimers observed by Tanaka et al. It is striking that
this translocation event is regulated by phosphorylation, providing a first insight
into the signaling pathways that control the dynamic regulation of cadherin-based
adhesion at the synapse (Murase et al. 2002).
PROTOCADHERINS Like the classical cadherins, protocadherins contain extracellular EC domains; however, their cytoplasmic domains are different. Most attention
has recently focused on the α-, β-, and γ -protocadherin families because they contain a large number of isoforms and show an unusual genomic organization. In
the human genome, 52 individual genes were identified, which are clustered in
one region of chromosome 5 (Wu & Maniatis 1999). Based on sequence comparisons, these genes were grouped into the α-, β-, and γ -families. Within one family,
individual members have variable extracellular sequences but share an identical
cytoplasmic tail. It is an exciting question how the diversity of this protein family
is generated. Protocadherin genes have unusually large exons. The large variable
extracellular and membrane-spanning domains are encoded by single exons that
are transcribed from individual promoters. These exons are then combined by cissplicing with three small exons encoding the cytoplasmic tail (Tasic et al. 2002,
Wang et al. 2002).
The large sequence diversity of protocadherins and their potential role in cellcell signaling suggested that these proteins might be involved in specifying neuronal circuits. Studies of the mouse α-protocadherin family (originally termed
cadherin-neuronal receptors) revealed that individual family members are indeed
expressed in specific subsets of neurons (Kohmura et al. 1998). Furthermore,
at least one of these proteins (CNR1) localizes to synapses where it interacts directly with the nonreceptor tyrosine kinase fyn, which itself has been implicated in
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MECHANISMS OF CNS SYNAPSE FORMATION
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synaptic function (Yagi et al. 1993, Kohmura et al. 1998). It is still unclear whether
any of the α-, β-, and γ -protocadherins mediate homophilic interactions like the
classical cadherins do. In fact, α-protocadherins may interact in a heterophilic
manner with the extracellular protein reelin and transduce extracellular signals
to the src-family kinases (Senzaki et al. 1999). How cell-specific protocadherinmediated signaling might contribute to the formation of synaptic circuits during
development remains to be shown in the future.
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Other Trans-Synaptic Signaling Molecules
Besides the signaling systems described above, several additional synaptic receptor complexes have been characterized that may contribute to synapse formation.
Among those are integrins (Chavis & Westbrook 2001, Grotewiel et al. 1998),
MHC class I molecules (Huh et al. 2000), syndecans (Ethell et al. 2001), Trk
receptors (Alsina et al. 2001, Rico et al. 2002), insulin receptors (Abbott et al.
1999), and agrin (Ferreira 1999, Gingras et al. 2002). Another recently identified
factor is the protein neural-activity-regulated pentraxin (NARP), which was obtained in a screen for activity-induced genes (Tsui et al. 1996). Elegant in vitro
experiments demonstrated that NARP released from the presynaptic cell binds to
the extracellular domain of AMPA receptors and induces clustering of this receptor
(O’Brien et al. 1999, 2002). NARP may therefore represent a presynaptic factor
that can induce some aspects of postsynaptic differentiation comparable to agrin
at the NMJ.
Another interesting synaptic signaling molecule is neuregulin, which has been
extensively studied at the NMJ. Nerve-derived neuregulin stimulates acetylcholine
receptor synthesis in the muscle and may thereby promote muscle differentiation
(Fischbach & Rosen 1997). Neuregulin and its receptors, the Erb-family tyrosine
kinases, also localize to CNS synapses where they mediate trans-synaptic signaling (Huang et al. 2000, Sandrock et al. 1995). How exactly neuregulin signaling
affects synapse formation in the CNS is unclear; however, it has been suggested
that presynaptic neuregulin can induce the upregulation of various neurotransmitter receptor subunits in the postsynaptic cell by signaling through Erb receptors
(Ozaki et al. 1997, Rieff et al. 1999). Neuregulin signaling may therefore regulate
expression of synaptic genes in a postsynaptic neuron in a manner similar to that
described for muscles during innervation (Fischbach & Rosen 1997).
PARALLEL PATHWAYS FOR SYNAPSE
FORMATION IN THE CNS
The primary model for studying the molecular mechanisms of synapse formation has been the NMJ, where agrin released for the ingrowing axon binds to a
MuSK/MASC receptor complex on the muscle. MuSK signaling through the cytoplasmic molecule rapsyn then leads to the accumulation of ACh-receptors at the
nerve muscle contact sites. It is remarkable that lack of any of these three signaling
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molecules results in a complete block of NMJ formation (Burden 1998, Sanes &
Lichtman 1999). Despite significant efforts, factors that are absolutely essential
for the differentiation of CNS synapses have not been identified yet. This could
mean that the crucial factors still remain to be discovered. However, it is also
possible that synapse formation in the CNS occurs via multiple parallel pathways
that are partially redundant. If, during development, one pathway is inactivated
by experimental manipulation, mechanisms of synaptic homeostasis might result
in an upregulation of the other signaling systems to generate the desired synaptic
connectivity of a cell (Davis & Bezprozvanny 2001).
It is interesting that several of the trans-synaptic signaling systems converge
into common cytoplasmic scaffolds and effectors. For example, SynCAM and
Neurexins, which both can direct the assembly of presynaptic terminals, interact
with the multivalent scaffolding molecule CASK (Biederer et al. 2002, Hata et al.
1996, Maximov et al. 1999). Furthermore, beta-catenin, which links cadherins to
the cytoskeleton, also interacts with Veli/Lin-7 (Perego et al. 2000), a component
of the Veli/Mint/CASK complex (Borg et al. 1998, Butz et al. 1998). Incipient cell
junctions formed by Neurexins, which couple to CASK, might therefore recruit
beta-catenin and subsequently cadherins. Similar cross talk of cell-adhesion systems has been previously observed for cadherins and nectins in nonneuronal cells
(Tachibana et al. 2000).
The scaffolding molecule PSD-95 might represent an important linker between
different trans-synaptic signaling systems in the postsynaptic cell. This cytoplasmic protein contains independent binding sites for Neuroligins and NMDAreceptor subunits (Irie et al. 1997, Kornau et al. 1995). NMDA receptors can in
turn interact with EphB receptors, and PSD-95 may therefore link the Neuroligin/Neurexin and EphB/Ephrin systems. Although the formation of such large
lateral complexes still needs to be directly demonstrated, it is to be expected
that synapse formation during development involves cooperative interactions between multiple signaling systems. Secreted factors such as WNTs and Semaphorins
appear to control the initial axon-target contacts. Subsequent direct interactions
between pre- and postsynaptic cells can probably be initiated by several of the cellsurface receptor systems. Signaling might then induce the assembly of a functional
platform of scaffolding molecules that recruits additional signaling molecules, resulting in a stepwise assembly and strengthening of the incipient contacts. Should
contacts be formed with an inappropriate target, the additional receptor systems
will not match and cannot engage in productive signaling. Consequently, such
contacts would not be sufficiently stabilized and therefore would be disassembled
(see Figure 2).
What is the advantage of several parallel pathways for synapse formation in
the CNS? Appropriately controlled synaptogenesis is of crucial importance for
nervous system function. The presence of multiple partially redundant pathways
makes a process very robust. However, at the same time it enables the cell to
selectively regulate individual pathways in response to physiological stimuli and
thereby to regulate specific aspects of synaptic function. Such mechanisms should
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MECHANISMS OF CNS SYNAPSE FORMATION
503
generate the degree of flexibility required not only for the ability of a single neuron
to form a multitude of different synaptic connections but also for the plasticity of
individual synapses, which underlies the higher functions of the CNS.
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ACKNOWLEDGMENTS
I am grateful to Angela Eickhorst and Dr. Mat for comments on the manuscript
and to my colleagues at Columbia University for their support. Research in our
laboratory was supported by funds from the Searle Scholar Program, the Alfred
P. Sloan Foundation, the Esther A. and Joseph Klingenstein Fund, and the Christopher Reeve Paralysis Foundation.
The Annual Review of Neuroscience is online at http://neuro.annualreviews.org
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Annual Review of Neuroscience
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CONTENTS
PAIN MECHANISMS: LABELED LINES VERSUS CONVERGENCE IN
CENTRAL PROCESSING, A.D. (Bud) Craig
CODING OF AUDITORY SPACE, Masakazu Konishi
DECIPHERING THE GENETIC BASIS OF SPEECH AND LANGUAGE
DISORDERS, Simon E. Fisher, Cecilia S.L. Lai, and Anthony P. Monaco
EPIDEMIOLOGY OF NEURODEGENERATION, Richard Mayeux
NOVEL NEURAL MODULATORS, Darren Boehning and Solomon H. Snyder
THE NEUROBIOLOGY OF VISUAL-SACCADIC DECISION MAKING,
Paul W. Glimcher
COLOR VISION, Karl R. Gegenfurtner and Daniel C. Kiper
NEW INSIGHTS INTO THE DIVERSITY AND FUNCTION OF NEURONAL
IMMUNOGLOBULIN SUPERFAMILY MOLECULES, Geneviève Rougon
and Oliver Hobert
1
31
57
81
105
133
181
207
BREATHING: RHYTHMICITY, PLASTICITY, CHEMOSENSITIVITY,
Jack L. Feldman, Gordon S. Mitchell, and Eugene E. Nattie
PROTOFIBRILS, PORES, FIBRILS, AND NEURODEGENERATION:
SEPARATING THE RESPONSIBLE PROTEIN AGGREGATES FROM THE
INNOCENT BYSTANDERS, Byron Caughey and Peter T. Lansbury, Jr.
SELECTIVITY IN NEUROTROPHIN SIGNALING: THEME AND VARIATIONS,
Rosalind A. Segal
BRAIN REPRESENTATION OF OBJECT-CENTERED SPACE IN MONKEYS
AND HUMANS, Carl R. Olson
GENERATING THE CEREBRAL CORTICAL AREA MAP, Elizabeth A. Grove
and Tomomi Fukuchi-Shimogori
239
267
299
331
355
INFERENCE AND COMPUTATION WITH POPULATION CODES,
Alexandre Pouget, Peter Dayan, and Richard S. Zemel
381
MOLECULAR APPROACHES TO SPINAL CORD REPAIR, Samuel David and
Steve Lacroix
411
CELL MIGRATION IN THE FOREBRAIN, Oscar Marı́n and
John L.R. Rubenstein
viii
441
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Annual Reviews
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CONTENTS
ix
CELL-CELL SIGNALING DURING SYNAPSE FORMATION IN THE CNS,
Peter Scheiffele
485
SIGNALING AT THE GROWTH CONE: LIGAND-RECEPTOR COMPLEXES
AND THE CONTROL OF AXON GROWTH AND GUIDANCE,
Andrea B. Huber, Alex L. Kolodkin, David D. Ginty, and
Jean-François Cloutier
509
NOTCH AND PRESENILIN: REGULATED INTRAMEMBRANE PROTEOLYSIS
LINKS DEVELOPMENT AND DEGENERATION, Dennis Selkoe and
Annu. Rev. Neurosci. 2003.26:485-508. Downloaded from arjournals.annualreviews.org
by ETHNOLOGISCHES SEMINAR on 02/05/09. For personal use only.
Raphael Kopan
THE BIOLOGY OF EPILEPSY GENES, Jeffrey L. Noebels
HUMAN NEURODEGENERATIVE DISEASE MODELING USING
DROSOPHILA, Nancy M. Bonini and Mark E. Fortini
PROGRESS TOWARD UNDERSTANDING THE GENETIC AND
BIOCHEMICAL MECHANISMS OF INHERITED PHOTORECEPTOR
DEGENERATIONS, Laura R. Pacione, Michael J. Szego, Sakae Ikeda,
Patsy M. Nishina, and Roderick R. McInnes
565
599
627
657
CELL BIOLOGY OF THE PRESYNAPTIC TERMINAL, Venkatesh N. Murthy
and Pietro De Camilli
701
INDEXES
Subject Index
Cumulative Index of Contributing Authors, Volumes 17–26
Cumulative Index of Chapter Titles, Volumes 17–26
ERRATA
An online log of corrections to Annual Review of Neuroscience chapters
(if any, 1997 to the present) may be found at http://neuro.annualreviews.org/
729
739
743