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Synaptic Cell Adhesion

Markus Missler1, Thomas C. Su¨dhof2, and Thomas Biederer3

1Department of Anatomy and Molecular Neurobiology, Westfa¨lische Wilhelms-University, 48149 Mu¨nster, Germany 2Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305 3Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520 Correspondence: [email protected]

Chemical are asymmetric intercellular junctions that mediate synaptic trans- mission. Synaptic junctions are organized by trans-synaptic cell adhesion molecules bridg- ing the synaptic cleft. Synaptic cell adhesion molecules not only connect pre- and postsyn- aptic compartments, but also mediate trans-synaptic recognition and signaling processes that are essential for the establishment, specification, and plasticity of synapses. A growing number of synaptic cell adhesion molecules that include and , Ig- domain proteins such as SynCAMs, receptor phosphotyrosine kinases and phosphatases, and several leucine-rich repeat proteins have been identified. These synaptic cell adhesion molecules use characteristic extracellular domains to perform complementary roles in or- ganizing synaptic junctions that are only now being revealed. The importance of synaptic cell adhesion molecules for function is highlighted by recent findings implicating several such molecules, notably neurexins and neuroligins, in schizophrenia and autism.

SYNAPTIC CELL ADHESION tural studies have shown that the material cross- ing the synaptic cleft is periodically organized ynapses constitute highly specialized sites of and composed of highly concentrated proteina- Sasymmetric cell–cell adhesion and intercel- ceous material (Lucic et al. 2005; Zuber et al. lular communication. The very first studies of 2005). ultrastructure already described their The spatiallyand temporallycoordinated as- “triple structure” comprised of pre- and postsyn- sembly of pre- and postsynaptic membranes is aptic membrane specializations and synaptic consistent with instructive roles of synaptic cell cleft material, concluding that “the thickened adhesion in synapse development. The precise regions show special adhesive properties (Gray overlap of pre- and postsynaptic specializations 1959).” Adhesion is an important structural additionally indicates that interactions across aspect of synapses as evidenced by the fact that the cleft delineate their mutual boundaries pre- and postsynaptic specializations remain (Schikorski and Stevens 1997). The regular tightly attached upon biochemical fractionation width of the synaptic cleft further shows that ad- (Gray and Whittaker 1962). Indeed, ultrastruc- hesive interactions may act as “molecular rulers”

Editors: Morgan Sheng, Bernardo Sabatini, and Thomas Su¨dhof Additional Perspectives on The Synapse available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved. Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a005694

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M. Missler et al.

to define its span (Palade and Palay 1954; Gray ture synapses. The molecular assembly stage 1959). During , axonal growth includes recruitment of synaptic vesicles, active cones and their dendritic targets frequently ex- zones, and postsynaptic density structures to a tend filopodia to form initial contacts (Cooper developing synaptic contact, resulting in an ana- and Smith 1992). Synaptic membrane special- tomically identifiable synapse, but does not in izations assemble at these contacts as ultrastruc- itself produce a functional synapse. Functional- turally defined by synaptic vesicles, electron- ity of a synapse is achieved with the organiza- dense cleft material, and thickened postsynap- tion of its molecular components during the tic membranes, and the intercellular distance functional specification stage, which also con- widens from an initial 13 nm interstitial space fers specific properties to a synapse. Synaptic to the final 20 nm “cleft” (Rees et al. 1976). Fi- plasticity is viewed here as an extension of syn- nally, mature synapses are subject to activity- apse formation that often involves changes akin dependent structural and functional plasticity to the molecular assembly and functional speci- mechanisms that remodel them, and that may fication of a synapse. All of these stages likely re- be regulated by synaptic cell adhesion (Toni quire synaptic cell adhesion molecules and are et al. 1999; Knott et al. 2002). Moreover, syn- mediated by sequential protein–protein interac- apses continue to be formed and eliminated tions, and many of these processes are probably throughout the lifetime of an organism. Synapse activity dependent. The adhesive mechanisms formation and elimination are most active dur- and signaling pathways guiding synapse forma- ing the postnatal period of development during tion are only now beginning to be recognized. which a vertebrate brain acquires maturity, but are continuously operating to support learning and processes as well as regenerative TOOL BOX OF SYNAPTIC CELL ADHESION: MULTIPLE DOMAINS, BINDING processes in disease. PROPERTIES, AND FUNCTIONS The proteins crossing the synaptic cleft are collectively referred to as synaptic cell adhesion Although synaptic celladhesion molecules com- molecules (Akins and Biederer 2006; Piechotta prise a number of proteins that are specialized et al. 2006), a somewhat misleading term be- for distinct functions in the recognition, molec- cause these molecules most likely do not only ular assembly, and/or specification of chemical function in cell adhesion, but also in intercel- synapses, their adhesive and functional specific- lular trans-synaptic signaling. Criteria for a ity is based on a limited number of extracellular synaptic include their domains. These domains are often assembled localization to synapses at one or more stages into repeated units, which may not only increase of development, functions in cell–cell interac- the number of possible interactions but also al- tions, and evidence for altered synapse forma- lows them to protrude into or cross the synaptic tion and/or function after the loss-of-function cleft and provide for mechanical stability. Below, or increased expression of these proteins. we discuss these domains as building blocks of In the present article, we will focus on the synaptic cell adhesion. contributions of synaptic cell adhesion mole- Immunoglobulin- (Ig-) domains. Ig-domains cules throughout the lifetime of a synapse. Syn- are animal cell adhesion domains that most apse formation is a complex multistage process. frequently bind to other Ig-domains, either as A conceptual division of synapse formation homo- and heterophilic complexes. Ig-domains into four stages postulates that initial establish- are composed of a b-sandwich that is often sta- ment of synaptic contacts is followed by assem- bilized by a disulfide bond; most cell-adhesion bly of the pre- and postsynaptic molecular ma- molecules containing Ig-domains also contain chinery, functional specification of the incipient fibronectin III (FnIII) domains with a similar synapses, and finally (Fig. 1). b-sandwich fold. Contact establishment involves recognition of domains. Cadherin domains are pre- and postsynaptic neurons at the site of fu- characterized by an all-b fold, and always occur

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Synaptic Cell Adhesion

I) Establishment II) Assembly

III) Specification IV) Plasticity

= Heterophilic trans-synaptic = Homophilic trans-synaptic cell adhesion molecules cell adhesion molecules

Figure 1. Synaptic cell adhesion and synaptic function. Synaptic cell adhesion involves multiple, partially over- lapping processes. (I) Initial establishment of axo-dendritic contacts may require heterophilic and homophilic cell adhesion molecules to recognize appropriate pre- and postsynaptic partners. During the molecular assembly (II) and functional specification (III) of synapses, synaptic cell adhesion molecules mediate recognition, physical cell–cell adhesion, and serve as anchor proteins to cluster or recruit receptors and components of the pre- and postsynaptic signaling machinery. Their action eventually leads to synapses with distinct physiological proper- ties as exemplified by distinct responses to the same stimuli. (IV) In adaptive events, for example during memory formation, synaptic cell adhesion molecules also may contribute to structural changes and functional synaptic plasticity such as long-term potentiation or depression.

in multiple copies connected by a linker that Laminin A, , and sex hormone-bind- binds 2–3 Ca2þ-ions, which leads to the char- ing protein (LNS) domains (a.k.a. laminin G- acteristic curvature of cadherin extracellular do- like LG-domains). LNS domains are composed mains (Pokutta and Weis 2007). Cadherin- of a lectin-like b-sandwich with a conserved mediated interactions are Ca2þ-dependent and Ca2þ-binding site at the variable rim (Rudenko often homophilic. et al. 2001; Arac¸et al. 2007; Reissner et al. 2008).

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M. Missler et al.

In a-neurexins and neurexin-related CASPR 2011). In vertebrates, different neurexin isoforms proteins, several LNS domains are present in a and splice variants are differentially expressed, series, often with interspersed rigid EGF-like consistent with the notion that they mediate a rec- domains; this arrangement results in a complex ognition code (Ullrich et al. 1995). L-shaped structure with two hinge-regions in Neuroligins are postsynaptic type I mem- neurexin-1a (Fig. 2) (Chen et al. 2011; Miller brane proteins that were identified as neurexin et al. 2011). ligands (Ichtchenko et al. 1995, 1996). Neuroli- Leucin-rich repeats (LRRs). LRRs are not au- gins are expressed from four genes in vertebrates tonomously folded domains but 20–30 residue (-1 to -4, abbreviated here as NL1 to sequences with a characteristic leucine-rich se- NL4). Primates contain nonrecombining copies quence pattern. Tandem repeats of LRRs, flanked of neuroligin-4 on the X- and Y-chromosomes, by characteristic amino- and carboxy-terminal with the Y-chromosomal copy often referred to sequence motifs, fold into curved solenoid as neuroligin-5. a- and b-neurexins both bind structures stabilized by extensive hydrophobic to all neuroligins to form cell adhesion com- interactions of their leucine residues. plexes (Boucard et al. 2005). In contrast to neu- rexins, neuroligins are specifically localized to particular synapses. NL1 is only present at exci- NEUREXIN AND NEUROLIGIN tatory synapses (Song et al. 1999), NL2 and NL4 INTERACTIONS INSTRUCT SYNAPSE at inhibitory synapses (Varoqueaux et al. 2004; SPECIFICATION AND FUNCTION Hoon et al. 2011), whereas NL3 is present at Neurexins were identified as a presynaptic re- both excitatory and inhibitory synapses (Bu- ceptor for a-latrotoxin, a spider toxin that causes dreck and Scheiffele 2007). The extracellular massive synaptic vesicle (Ushkaryov sequence of neuroligins is largely composed of et al. 1992, 1993, and 1994). Neurexins are pre- a single esterase-like domain that forms a con- synaptic type I membrane proteins with a large stitutive dimer, whereas their cytoplasmic tails extracellular sequence and a short cytoplasmic contain a PDZ-domain binding sequence that tail. Vertebrates contain three neurexin genes recruits PSD-95 and other PDZ-domain pro- (neurexin-1 to -3, abbreviated here as Nrx1 to teins (Irie et al. 1997), and tyrosine-based mo- Nrx3) that produce from independent promot- tif that binds to gephyrin (Poulopoulos et al. ers a longer a- and a shorter b-neurexin iso- 2009). It is currently unclear how neuroligins form. Extracellularly, a-neurexins contain six are specifically recruited to excitatory or inhib- LNS domains with three interspersed EGF-like itory synapses because all neuroligins similarly domains, whereas b-neurexins only contain a interact in vitro with excitatory- and inhibitory- single LNS-domain that is identical to the sixth specific cytoplasmic proteins (PSD-95 and ge- LNS-domain of the corresponding a-neurexin phyrin, respectively). (Fig. 2) (Ushkaryov et al. 1992, 1993, and 1994). Binding of neurexins to neuroligins is me- Moreover, neurexins are extensively alterna- diated by the sixth LNS domain of a-neurexin tively spliced at five conserved sites in their ex- and the single LNS domain of b-neurexin, and tracellular region, creating potentially thou- likely forms a trans-synaptic complex. Although sands of isoforms (Ullrich et al. 1995; Tabuchi a- and b-neurexins bind to neuroligins via the and Su¨dhof 2002). Intracellularly, the short same LNS domain, their binding properties cytoplasmic tails of neurexins contain PDZ-do- are different (Boucard et al. 2005; Reissner et al. main binding sequences that bind to CASK (a 2008). Moreover, different neurexin and neuroli- hybrid kinase/MAGUK protein that was identi- gin isoforms show distinct binding affinities. fied as a neurexin-interacting protein; Hata et al. Most importantly,however,bindingofneurexins 1996) and to protein 4.1 in a trimeric complex and neuroligins is tightly regulated by alter- (Biederer and Su¨dhof 2001). Neurexins are evolu- native splicing, especially at the splice site 4 in tionarily conserved and pan-neuronallyexpressed the shared LNS-domain of a- and b-neurexins (Tabuchi and Su¨dhof 2002; Haklai-Topper et al. (Ichtchenko et al. 1995; Boucard et al. 2005).

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Synaptic Cell Adhesion

α-Neurexin Synaptic vesicle β-Neurexin Calcium channel

Neuroligin Postsynaptic receptor

α-Neurexin knockouts Neuroligin knockouts

• Mini (mPSC) frequency • Mini (mPSC) frequency and amplitude (Nlgn2) • Release probability • Basal synaptic transmission • Calcium currents • Postsynaptic receptor clustering • Density of inhibitory synapses • NMDA/AMPA receptor ratio • Behavioral impairments in single KO • Behavioral impairments in single KO

Figure 2. The case of neurexins/neuroligins. Presynaptic neurexins (red) and postsynaptic neuroligin dimers (green) associate in a Ca2þ-dependent manner to form a prototypical trans-synaptic complex that reflects the asymmetric architecture of chemical synapses. The sixth LNS domain of a-neurexins and the corresponding single LNS domain of b-neurexins both bind to neuroligins via hydrophobic interactions that bury the Ca2þ-ion in the interface. Genetic deletion studies in mice revealed the essential role of both gene families at synapses be- cause triple knockouts of either neurexin-1a/2a/3a or of neuroligin-1/2/3 are perinatally lethal, and show dra- matic impairments in synaptic function as summarized in the text box (arrows indicate direction of change). Note that a-neurexins and neuroligins are not essential for the formation of synaptic contacts in the brain. The space filling models of the extracellular sequences of neurexins and neuroligins are based on homology modeling of available crystal data, and are presented approximately to scale in the synaptic cleft. (Full-length structures of synaptic cell adhesion proteins and of postsynaptic receptors as shown in Figures 2–4 were mod- eled using coordinates from the protein data bank (http://www.pdb.org), models from ModBase (http://mod- base.compbio.ucsf.edu), SWISS-MODEL Repository (http://swissmodel.expasy.org/repository/) and Phyre (http://www.sbg.bio.ic.ac.uk/~phyre/). Missing structures were modeled manually using BLAST2MODEL (http://dunbrack.fccc.edu) and program SPDPV (http://spdbv.vital-it.ch/). The complex structures were vi- sualized using the open source program pymol (http://sourceforge.net/projects/pymol/).

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M. Missler et al.

As summarized below, the same site of alterna- but no significant decrease in glutamatergic syn- tive splicing is also of central importance for apse density (Missler et al. 2003). Survival of the interactions of neurexins with other ligands. a-neurexin double-knockout mice is also com- Cell-based assays of synapse assembly showed promised,andanimalsreachingadulthoodshow that contact of dissociated neurons with neuroli- lowered inhibitory synapse densities, whereas gin-expressing nonneuronal cells results in the excitatory synapse numbers remain unchanged recruitment of presynaptic markers (Scheiffele (Missler et al. 2003). Even single a-neurexin et al. 2000), whereas contact of neurons with knockout mice show a survival phenotype, and neurexin-expressing nonneuronal cells produces neurexin-1a single knockout mice display de- recruitment of postsynaptic markers (Graf et al. creased excitatory transmission in the hippo- 2004; Nam and Chen 2005). The activity of neu- campus and behavioral deficits (Etherton et al. roligin in this artificial synapse formation assay 2009). In addition, the triple a-neurexin knock- depends on binding to its presynaptic partner out mice show changes in postsynaptic NMDA neurexin (Ko et al. 2009a). Although this cell- receptor function (Kattenstroth et al. 2004), based assay does not differentiate between syn- and neurexins physically bind to GABAA-recep- apse-inducing and synapse-stabilizing activities tors and acetylcholine receptors (Cheng et al. of a molecule, it provides a powerful approach to 2009; Zhang et al. 2010). Despite this wealth of dissecting the structure/function relationships information, however, the precise roleof neurex- of synaptic cell adhesion molecules. ins remains incompletely understood; although Interestingly,overexpressionof neuroligins in the data are best explained by an organizing neurons leads to dramatic increases in neuronal function of neurexins in coordinating the re- synapse density (Chih et al. 2005; Boucard et al. cruitment of calcium channels and components 2005), with specificeffectof neuroligin-1onexci- of the release machinery to presynaptic termi- tatory and neuroligin-2 on inhibitory synapses nals with the assembly of postsynaptic special- (Chubykin et al. 2007). The increased synapse izations, the molecular mechanisms involved re- density induced by neuroligin overexpression main uncharacterized. As we will see below, one likely reflects a stabilization of transient synaptic reason for this uncertainty is the bewildering contacts by neuroligins because it is activity-de- number of extracellular trans-synaptic interac- pendent (Chubykin et al. 2007; Ko et al. 2011). tion partners for neurexins that extend beyond Similar changes were also observed upon trans- neuroligins—themselves central players in syn- genic overexpression of neuroligins in mice apse organization—to proteins such as leucine- (Hines et al. 2008; Dahlhaus et al. 2010), whereas rich repeat transmembrane proteins (LRRTMs), deletion of neuroligins does not decrease syn- cerebellins, and dystroglycan. apse density (Varoqueaux et al. 2006; see discus- Triple knockout of NL1, NL2, and NL3 also sion below). At least in the case of neuroligin-1, results in perinatal lethality caused by an im- the increase in neuronal synapse density induced pairment of transmission (Varoqueaux et al. by overexpression is independent of the cyto- 2006). Similar to the triple a-neurexin knock- plasmic tail of neuroligin-1, its dimerization, or out, the triple neuroligin knockout has no ma- its binding to neurexins (Ko et al. 2009a, 2011). jor effect on overall synapse numbers, again Studies of knockout mice have revealed vital supporting a role of this protein family in or- functions for a-neurexins and neuroligins in ganizing synapses. Consistent with its localiza- organizing synapses. The combined knockout tion, the single knockout of NL1 selectively im- of all three a-neurexins is lethal at birth, likely pairs the strength of excitatory synapses and because of a strong impairment in neurotrans- decreases the ratio of NMDA- to AMPA-recep- mitter release (Fig. 2) (Missler et al. 2003; Zhang tor mediated responses, whereas single knock et al. 2005a). Specifically, triple a-neurexin knock- out of NL2 selectively depresses inhibitory syn- out mice showed an almost complete abatement aptic transmission (Chubykin et al. 2007; Pou- of glutamatergic synaptic transmission in acute lopoulos et al. 2009). Interestingly, paired re- brainstem slices and in cultured cortical slices, cordings in the somatosensory cortex revealed

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Synaptic Cell Adhesion

that the NL2 knockout does not affect all in- teins that induce presynaptic terminals in hip- hibitory synapses equally, but selectively only pocampal neurons (de Wit et al. 2009; Ko et al. dampened inputs from fast-spiking interneu- 2009b; Siddiqui et al. 2010) and to cerebellins rons without decreasing connectivity (Gibson that participate in synapse formation at least et al. 2009). Thus, NL2 does not function as a in Purkinje cells (Uemura et al. 2010; Matsuda general organizer of all inhibitory synapses, but and Yuzaki 2011). The binding of LRRTMs to acts in a selected subset of inhibitory synapses neurexins is competitive with neuroligins be- in a neuron. Studies in Drosophila, Caenorhabdi- cause the binding site partly overlaps, and is tis elegans, and Aplysia support the notion that tightly regulated by alternative splicing at splice neurexins and neuroligins control synapse mor- site #4 (Fig. 3) (Ko et al. 2009b; Siddiqui et al. phology and composition, at least in inverte- 2010). Binding of cerebellins to neurexins is brates (Li et al. 2007; Banovic et al. 2010; Choi also controlled by alternative splicing at site 4, et al. 2011; Haklai-Topper et al. 2011; Sun et al. but here an insert in splice site 4 is required 2011). for binding to cerebellins (Uemura et al. 2010; In contrast to knockout studies, RNAi-me- Matsuda and Yuzaki 2011). Morever, Ca2þ is diated knockdowns have suggested in some required for binding of neurexins to neuroligins cases that acute loss-of-function of a single neu- and LRRTMs (Ichtchenko et al. 1995; Ko et al. rexin and neuroligin isoform results in a dra- 2009b), but not for binding of neurexins to cer- matic loss of synapses in rodent neurons (e.g., ebellins (Uemura et al. 2010; Matsuda and Yu- see Chih et al. 2003; de Wit et al. 2009; Shipman zaki 2011). et al. 2011). However, other studies found no Recent systematic studies explored the im- effect of RNAi-mediated knockdown of single portance of the neurexin-binding partners ne- or multiple neuroligin isoforms on synapse den- uroligin-1 and -3 vs. LRRTM2 and LRRTM3 sity (Ko et al. 2011; Zhang et al. 2010), evenwhen at excitatory synapses in cultured neurons (Ko performed in vivo (Soler-Llavina et al. 2011). et al. 2011) and in vivo (Soler-Llavina et al. ApotentialproblemwithRNAi-mediatedknock- 2011). Only a combined loss-of-function of down experiments are off-target effects, as shown neuroligin-1 and -3 (which are the only neuro- for example for knockdown of LRRTMs (Ko ligins at excitatory synapses) and LRRTM2 and et al. 2011). A further issue in RNAi-mediated LRRTM3 (which are the only LRRTMs ex- knockdowns of neuroligins, LRRTMs, and sim- pressed at significant levels in the hippocampal ilar molecules is that classical rescue experi- neurons examined) suppressed excitatory but ments are not possible because overexpression not inhibitorysynapse densities in cultured neu- of the target molecules used for rescue by itself rons but not invivo. Interestingly,the decrease in causes a gain-of-function phenotype. It is possi- synapse density induced by the loss-of-function ble that genetic knockouts of neuroligins and of neuroligins and LRRTMs in cultured neurons a-neurexins are partly developmentally compen- was completely activity-dependent, similar to sated, such that some phenotypes are not present the increase induced by overexpression (Ko et al. in constitutive knockouts (such as a loss of syn- 2011). In these experiments, “knockdown” neu- apses) whereas others are (such as a loss of syn- rons were in a competition for synapses with aptic function). Conditional knockout mice are surrounding wild-type neurons. Overall, these now being generated to test this possibility. experiments together with the knockout data suggest that neurexin ligands do not act as syn- aptic glues, but as cell-autonomous, activity- OTHER LIGANDS FOR NEUREXINS dependent regulators of synapse function, with AND NEUROLIGINS their dysfunction leading to synapse elimination Neurexins and neuroligins not only interact with in some circumstances. each other, but also with other proteins (Fig. 3). a-Neurexins also bind to dystroglycan, which Neurexins bind to at least two other synapse-or- is abundantly expressed in neurons (Sugita et ganizing proteins, the LRRTM membrane pro- al. 2001), and to the neuropeptide-like protein

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M. Missler et al.

Neurexophilin

α β δ -, -Dystroglycan LRRTM2 GABAA receptor Cerebellin, GluR 2

Figure 3. Neurexins as synaptic anchors for macromolecular complexes. Because of the versatile nature of their LNS domains, a- and b-neurexins can interact with several binding partners (see insets) that either compete for the same interaction site such as neuroligin-1 and LRRTM2, or may bind at completely different sites such as neurexophilin. Because neuroligins form dimers, mixed complexes of a- and b-neurexins with neuroligin may exist, and may even recruit additional binding partners of a-neurexins, possibly leading to large multimo- lecular clusters. Direct or indirect association with ligand- or voltage-dependent ion channels (e.g., GABAAR, GluR, NMDAR, CaV2.x, see text for discussion) provides a means of determining synaptic properties or mod- ulating synaptic strength. The space filling models of neurexins and their binding partners are based on homol- ogy modeling of available crystal data, and are presented approximately to scale in the synaptic cleft.

neurexophilin (Missler et al. 1998). Both inter- herin in brain, is localized to sites surround- act with the second LNS domain of a-neurex- ing synapses (Uchida et al. 1996). It does not ins. Moreover, neuroligins exert neurexin-inde- control synapse number and is not involved in pendent synapse-organizing functions (Ko et al. synapse formation as such but likely plays broad 2009a; Banovic et al. 2010) suggesting that ad- modulatory roles in synapse development (Ju¨ng- ditional synaptic partners for neuroligins must ling et al. 2006). N-cadherin accumulates at exist. nascent synapses with a delay after axo-dendritic contact (Benson and Tanaka 1998), and con- tributes to the structural maturation of postsyn- INFLUENCE EARLY SYNAPSE aptic sites through signaling (Togashi DEVELOPMENT AND IMPACT SYNAPTIC et al. 2002; Bamji et al. 2003; Elia et al. 2006). PLASTICITY Synaptic activity drives N-cadherin into spines, Classical cadherins are among the best-studied the postsynaptic elements of excitatory synap- adhesion molecules and also contribute to syn- ses, and stabilizes the structural changes that aptic cell adhesion. They contain five extracellu- occur during LTP in developing and mature lar cadherin repeat domains (EC1–5), with the synapses (Bozdagi et al. 2010; Mendez et al. amino-terminal EC1 domain mediating adhe- 2010). This homophilic adhesion molecule also sion in trans (Fig. 4) (Pokutta and Weis 2007). acts across the synaptic cleft to modulate pre- N-cadherin, the most prominent classical cad- synaptic plasticity (Ju¨ngling et al. 2006) and

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Synaptic Cell Adhesion

SynCAM SALM Organize excitatory synapses Cluster postsynaptic molecules

Presynaptic

Postsynaptic

N-Cadherin NCAM Modulate synaptic function Regulate synaptic plasticity

SynCAM1 knockout SynCAM1 overexpression

• Density of excitatory synapses • Density of excitatory synapses • PSD length • Mini (mEPSC) frequency • Mini (mEPSC) frequency • Induction of LTD • Induction of LTD • Spatial learning behavior • Spatial learning behavior

Figure 4. Complexes by synaptic cell adhesion molecule families. Trans-synaptic complexes also occur between members of the same synaptic cell adhesion molecule family. The examples shown here contain multimers of characteristic extracellular domains such as Ig-domains (e.g., in SynCAM), EC domains (e.g., in N-cadherin), or LRR repeats (e.g., in SALM). The actual combinatorial code is not always as simple as depicted in the diagram because homomeric as well as heteromeric (e.g., SynCAM 1-SynCAM 2) binding occurs, and there are instances in which synaptic cell adhesion molecules act without formation of a known bona fide trans-synaptic complex (e.g., in SALMs, or NCAMs). Complexes between members of synaptic cell adhesion molecule family affect di- verse aspects of synaptic function and plasticity. Although none of these gene families is essential for the estab- lishment of the majority of synaptic contacts in the brain, analyses of SynCAM 1 knockout and transgenic mice have pointed to an essential role in the formation of excitatory synapses as summarized in the text box below the synapse diagram (arrows indicate direction of change). The space filling models are presented approximately to scale.

reduced presynaptic N-cadherin adhesion alters family called flamingo (vertebrate homolog: synaptic vesicle recycling (Togashi et al. 2002). CELSR) contains multiple cadherin repeats and The synaptic functions of N-cadherin comple- has been implicated in specifying planar cell ment other properties of classical cadherins in polarity and synapse specificity (Formstone neuronal development, such as their cosegrega- 2010). Protocadherins constitute a large and di- tion with motor neuron pools that is indicative verse protein family with ubiquitouslyexpressed of conveying neuronal identity and may con- membersthat mayalso be present, at least in part tribute to neuronal connectivity (Price et al. at synapses. For example g-protocadherins are 2002). at least partly synaptic (Phillips et al. 2003), Although N-cadherin is the best-studied and are required for the postnatal survival of in- member of the cadherin family at synapses, terneurons in the spinal cord (Wanget al. 2002). other cadherin-related proteins are also likely This phenotype of neuronal lethality could be important for synapse assembly and function. alleviated by impairing apoptosis, allowing to In Drosophila, a GPCR of this cell adhesion show that the loss of the g-protocadherin gene

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cluster leads to synaptic deficits in mouse spinal tory synapse number and transmission and cord (Weineret al. 2005). Similarly, calsyntenins shortens synaptic membrane specializations. At are cadherin-related proteins that are enriched in mature synapses, SynCAM 1 negatively regulates postsynaptic densities, although their functions long-term depression and impacts spatial learn- remain uncharacterized (Hintsch et al. 2002). ing. Roles of SynCAM 1 in the wiring and plas- ticity of neuronal networks are supported by its unusually dynamic expression in the visual SynCAM, LAR-TYPE RECEPTOR cortex during adaptive changes of eye-specific PHOSPHOTYROSINE PHOSPHATASES, responses (Lyckman et al. 2008) and during AND OTHER IG-DOMAIN PROTEINS the restoration of synapses by spinal cord moto- Many Ig-domain proteins have been localized neurons following injury (Zelano et al. 2009). to synapses, with the most conclusive evidence The functions of other SynCAM family mem- provided for a synaptic role of SynCAMs and bers in the brain remain to be analyzed, but the of receptor phosphotyrosine phosphatases be- tight binding of SynCAM 2 to SynCAM 1, the longing to the LAR family. ability of SynCAM 2 to induce synapses, and SynCAM synaptic cell adhesion molecules the presence of SynCAM 3/-like molecule (also named Cadm or nectin-like molecules) 1 at axon terminal/glia cell contacts (Kakunaga promote excitatory but not inhibitory synapse et al. 2005) point to partiallyoverlapping roles in numbers (Fig. 4). The four members of this synapse development. vertebrate-specific gene family contain three ex- are a family of Ig-domain adhesion tracellular Ig-domains, a single transmembrane proteins that share the extracellular domain or- region, and intracellular FERM- and PDZ-do- ganization of SynCAM molecules but have differ- main-binding motifs whose similarities to those ent cytosolic partners. Asymmetric interactions of neurexins led to SynCAM identification (Bie- of nectins promote the formation of puncta ad- derer et al. 2002; Biederer 2006). SynCAM pro- herentia, adhesion sites similar to tight junc- teins are predominantly expressed in the brain tions that likely provide mechanical stability at and localize to pre- and postsynaptic sites (Bie- parasynaptic sites and at connections of spines derer et al. 2002; Thomas et al. 2008). to astrocytic processes, but the participation of SynCAM 1 localizes in developing neurons nectins in synapses remains to be elucidated to the surface of axonal growth cones and (Mizoguchi et al. 2002; Togashi et al. 2006). shapes them through its partner focal adhesion Receptor phospho-tyrosine phosphatases kinase (Nozumi et al. 2009; Stagi et al. 2010). (RPTPs) of the LAR family include LAR (leuko- Analogous to a “contact sensor” of growth cones, cyte-associated receptor), RPTPs,andRPTPd SynCAM 1 assembles rapidly at axo-dendritic (Chagnon et al. 2004). Their extracellular do- contacts into stable adhesion complexes, which mains are composed of three Ig-domains and then accumulate synaptic markers (Stagi et al. eight fibronectin type III repeats. LAR-type 2010). At maturing synapses, SynCAM pro- RPTPs have been implicated in synapse forma- teins form specific homo- and heterophilic tion via binding to their intracellular interac- complexes through their Ig-domains whose ad- tion partner a-liprin, although alternatively a hesive strength is regulated by site-specific N- presynaptic site of action (Zhen and Yin 1999; glycans, including sialic acid; and postsynaptic Kaufmann et al. 2002) and a postsynaptic site SynCAMs act across the synaptic cleft to pro- of action was suggested (Dunah et al. 2005). mote functional excitatory synapse number Extracellularly, two trans-synaptic ligands were (Fogel et al. 2007, 2010). Elevated SynCAM 1 in- described for this class of RPTPs, in both cases creases the number of functional excitatory suggesting a presynaptic localization of the synapses in a transgenic mouse model, and syn- RPTP: netrin-G ligands (Wooet al. 2009; see de- aptic SynCAM adhesion additionally mediates scription under LRR proteins below) and the synapse maintenance (Robbins et al. 2010). neurotrophin receptor TrkC (Takahashi et al. Conversely, the loss of SynCAM 1 reduces excita- 2011).

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Synaptic Cell Adhesion

In addition to SynCAMs and RPTPs, other and are also called LRRC4 (Zhang et al. 2005b). Ig-domain proteins such as contactins and The three vertebrate NGLs (NGL1-3) are type members of the NCAM/L1 family have been I membrane proteins composed of an extra- implicated in synapse formation and function cellular LRR sequence, a single Ig-domain, a (reviewed in the work of Dityatev et al. 2008; transmembrane region, and a short cytoplasmic Zuko et al. 2011). Presynaptically, NCAM iso- tail capable of binding PSD-95 (Wooet al. 2009). forms play important roles at developing neu- NGLs are localized to postsynaptic membranes, romuscular junctions, in which they control in which NGL1 and NGL2 are thought to inter- the distribution of release sites (Polo-Parada act with presynaptic netrin-G1 and -G2 (Kim et al. 2004) and promote the physiological mat- et al. 2006), and NGL3 with LAR-type RPTPs uration of vesicle recycling (Hata et al. 2007). (Wooet al. 2009). Mice lacking either netrin-G2 Postsynaptically, NCAM clustering influences or NGL2 show mild behavioral defects but are the assembly of cytoskeletal scaffolds (Sytnyk et viable and fertile, indicating that the netrin- al. 2006) and contributes to LTP (Muller et al. G/NGL system may serve primarily as a modu- 1996). latory signaling system for synapses (Zhang Finally, an important additional role of cell et al. 2008). adhesion is to instruct where synaptic sites are Apossible synaptogenic function of LRRTMs, formed. Several Ig-domain proteins have been whichwere identified by bioinformatics (Laure´n implicated in this role. For example, such an et al. 2003), was discovered in a systematic screen instructive role is mediated in the retina by forsynaptogenic proteinsusing theartificialsyn- the sidekicks and Dscam Ig-domain proteins, apse formation assay (Linhoff et al. 2009). Strik- which ensure proper lamina connectivity (Ya- ingly, protein-interaction studies subsequently magata et al. 2002, 2008). Similarly, in C. elegans revealed that LRRTMs bind to neurexins in a the Ig-domain proteins Syg-1 and Syg-2 are not splice-site 4-dependent manner (see discussion directly related to synapse formation, but guide above;deWitetal.2009;Koetal.2009b;Siddiqui synapse formation to the right place in one par- etal.2010).SingleknockoutofLRRTMshasonly ticular neuron (Shen et al. 2004). In a compara- minor phenotypes (Linhoff et al. 2009), and ble manner, adhesive interactions mediated by knockdown of all major LRRTMs expressed in the Ig proteins neurofascin and CHL1 spatially a particular type of neuron in vitro or in vivo define synapses formed by basket interneurons does not produce alossof synapses,butdecreases and stellate cell axons, respectively, onto Pur- AMPA-receptor dependent trafficking (Ko et al. kinje cells on a subcellular level (Ango et al. 2011; Soler-Llavina et al. 2011). As described 2004, 2008). above, the loss of synapses reported for one LRRTM2 shRNA construct (de Wit et al. 2009; Ko et al. 2011) likely reflects an off-target effect. LEUCINE-RICH REPEAT PROTEINS A third family of LRR-containing mem- ORGANIZE BOTH PRE- AND brane proteins with synapse-organizing func- POSTSYNAPTIC SITES tions in vertebrates are SALMs (reviewed in Nam et al. 2011). Five SALM genes are expres- Several families of LRR proteins were shown sed in vertebrates. SALMs are type I membrane to function at synapses, in particular LRRTMs, proteins composed of an amino-terminal LRR netrin-G ligands (NGLs), and synaptic adhe- domain, a single Ig-domain and fibronectin III sion-like molecules (SALMs, also known as Lrfn domain, a transmembrane region and a cyto- proteins). plasmic tail that binds to PSD-95 for SALM1- Netrin-G1 and –G2 are netrin isoforms unique 3, but not SALM4 and SALM5 (Ko et al. 2006; to vertebrates that are attached to axonal mem- Wang et al. 2006). On the extracellular side, branes by a GPI anchor (Nakashiba et al. 2002). SALM4 and SALM5 form homophilic com- As indicated by their name, NGLs were identi- plexes (Seabold et al. 2008), and at least a subset fied by binding to netrin-G1 (Lin et al. 2003), of SALMs may interact with AMPA- and/or

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M. Missler et al.

NMDA-type glutamate receptors (Ko et al. 2006; they also perform in many other cellular proc- Wang et al. 2006). Moreover, SALMs may influ- esses, and the specific trans-synaptic roles of ence neuronal development and neurite out- /Eph receptor interactions remain to be growth, but the precise role of SALMs in synap- elucidated. ses remains unclear. Other transmembrane receptor tyrosine ki- nases share important functions at excitatory synapses. These include Trk receptors, which me- TYROSINE KINASE RECEPTOR SIGNALING diate neurotrophin signaling and are necessary IN EXCITATORY SYNAPSE DEVELOPMENT for proper synapse density and ultrastructure, In addition to classical adhesion molecules, and modulate activity-dependent structural and transmembrane tyrosine kinase receptors have functional changes at synapses (Rico et al. 2002; been implicated in synapse formation. Notably, Luikart et al. 2005; Rex et al. 2007), in addition EphB receptor tyrosine kinases are thought to their noncatalytic role mediated by bind- to produce a postsynaptic signal upon extracel- ing to LAR-type RPTPs (Takahashi et al. 2011; lular binding of their ephrin ligands, and to see above). Signaling by the insulin receptor engage several small Rho family , in- also promotes synapse number and function cluding RhoA and Rac1, as a result, thereby re- as shown in the Xenopus optic tectum and alters modeling the of postsynaptic dendrite dynamics (Chiu et al. 2008). Another spines (Lai and Ip 2009). The combined dele- family of receptor tyrosine kinases, the ErbB tion of EphB1-3 receptors in mice strongly receptors, is known to act in the formation of reduces synapse density and alters the morphol- neuromuscular junctions. Roles in central syn- ogy of dendriticspines(Henkemeyeretal.2003). apses are emerging, with the ErbB4 ligand neu- A synapse-inducing role of EphB receptors was regulin-1 enhancing GABA release from cortical corroborated in cultured hippocampal neurons. interneurons (Woo et al. 2007). EphB2 receptor signaling from postsynaptic sitestriggers presynaptic differentiation through ephrin binding, which stabilizes a subset of ADDITIONAL SURFACE INTERACTIONS REGULATE SYNAPSE DEVELOPMENT AND synapses (Kayser et al. 2006). Similarly, postsyn- PHYSIOLOGY aptic EphB2 receptors engage presynaptic eph- rinB ligands to induce and mature retinotectal Integrins are another prominent class of adhe- synapses in Xenopus (Lim et al. 2008). EphB2 sion molecules that promote synapse matura- additionally may organize postsynaptic mem- tion (Chavis and Westbrook 2001). Integrins branes in cis through lateral interactions with also impact synaptic physiology as loss of their NMDA receptors (Dalva et al. 2000). However, b1 subunit impairs LTP (Chan et al. 2006; transmembrane ephrin ligands were also shown Huang et al. 2006). Trans-synaptic interactions to be present at excitatory postsynaptic sites are not limited to classic adhesion molecules, where they promote spine density and matura- though, as shown by the neuronal pentraxins. tion and AMPA receptor trafficking (Segura This protein family binds extracellularly to et al. 2007). Moreover, postsynaptic ephrinB3 AMPA receptors and can form trans-synaptic ligand in addition controls the number of complexes to organize excitatory synapse devel- dendritic shaft synapses, a subset of excitatory opment (O’Brien et al. 2002; Koch et al. 2010). synapses (Aoto et al. 2007). The activation of postsynaptic EphA receptors, which bind the SYNAPTIC CELL ADHESION AND GPI-anchored ephrinA ligands expressed in as- BRAIN DISORDERS trocytes, in contrast leads to spine retraction (Murai et al. 2003; Bourgin et al. 2007). Overall, Studies of synapse structure have not only pro- it seems likely that Ephrin/Eph receptor interac- vided crucial keys to understanding synapse tions are major determinants of synaptic func- development. They have also shown that the al- tion via cytoskeletal reorganizations, a role that tered morphology of excitatory synapses can be

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linked to neurological and neurodevelopmental ACKNOWLEDGMENTS disorders. Human genetic analyses of autism- Wethank H. Blum and C. Reissner for help with spectrum disorders both in hereditary cases illustrations, and members of the Biederer labo- and through genome-wide association studies ratory and C.R. for comments on the manu- point to a synaptic etiology. These analyses script. Workon synaptic cell adhesion molecules have established strong genetic links of muta- in the authors’ laboratories are supported by tions in synaptic cell adhesion molecules to grants from the NIH (grant R01 DA018928 to autism-spectrum disorders, notably in neuroli- T.B., and R01MH089054 and R37 MH052804 gins and neurexins (reviewed in Su¨dhof 2008). to T.C.S.), the Simons Foundation (SF177850 In the case of two autism-linked neuroligin mu- to T.C.S.),and the DFG (SFB 492-A16 to M.M.). tations, mouse models have corroborated the human genetic findings (Tabuchi et al. 2007; Ja- main et al. 2008). These results endorse the REFERENCES hypothesis that neurodevelopmental disorders can stem from synapse disorganization and im- Akins MR, Biederer T.2006. Cell–cell interactions in synap- balanced neuronal excitation and inhibition togenesis. Curr Opin Neurobiol 16: 83–89. Ango F, di Cristo G, Higashiyama H, Bennett V, Wu P, (Zoghbi 2003; Bourgeron 2009). Studies of syn- Huang ZJ. 2004. Ankyrin-based subcellular gradient of apticcell adhesion are thereforelikely to contrib- neurofascin, an immunoglobulin family protein, directs ute importantly to understanding both synaptic GABAergic innervation at purkinje axon initial segment. biology and human brain disorders. Cell 119: 257–272. Ango F, Wu C, Van der Want JJ, Wu P,Schachner M, Huang ZJ. 2008. Bergmann glia and the recognition molecule CHL1 organize GABAergic axons and direct innervation CONCLUDING REMARKS: FOUR of Purkinje cell dendrites. PLoS Biol 6: e103. OPEN QUESTIONS Aoto J, Ting P,Maghsoodi B, Xu N, Henkemeyer M, Chen L. 2007. Postsynaptic EphrinB3 promotes shaft glutamater- Synapse formation requires mechanisms that gic synapse formation. J Neurosci 27: 7508–7519. demarcate and align future synaptic sites, and Arac¸D, Boucard AA, O¨ zkan E, Strop P,Newell E, Su¨dhof TC, differentiate nascent synapses into maturity. As Brunger AT. 2007. Structures of Neuroligin-1 and the Neuroligin-1/Neurexin-1b complex reveal specific pro- reviewed in this work, a select group of synaptic tein-protein and protein-Ca2þ interactions. Neuron 56: cell adhesion and signaling proteins organizes 992–1003. these processes. However, we are only at the be- Bamji SX, Shimazu K, Kimes N, Huelsken J, Birchmeier W, ginning of an understanding of how synapses Lu B, Reichardt LF. 2003. Role of b-catenin in synaptic vesicle localization and presynaptic assembly. Neuron are formed and maintained. Four key questions 40: 719–731. stand out. First, do individual synapse-orga- Banovic D, Khorramshahi O, Owald D, Wichmann C, Riedt nizing proteins actually instruct synaptic cell T, Fouquet W, Tian R, Sigrist SJ, Aberle H. 2010. Droso- adhesion in vivo, or do the functions of trans- phila neuroligin 1 promotes growth and postsynaptic dif- ferentiation at glutamatergic neuromuscular junctions. synaptic interactions result from cooperativity Neuron 66: 724–738. among different adhesion molecules? Second, Benson DL, Tanaka H. 1998. N-Cadherin redistribution how do these trans-synaptic interactions act at during synaptogenesis in hippocampal neurons. J Neuro- mature synapses to alter plasticity and mainte- sci 18: 6892–6904. Biederer T. 2006. Bioinformatic characterization of the nance? Third, is the functional role of synapse- SynCAM family of immunoglobulin-like domain-con- organizing molecules strictly defined, or does it taining adhesion molecules. Genomics 87: 139–150. change during the lifetime of a synapse? Fourth, Biederer T, Su¨dhof TC. 2001. CASK and protein 4.1 sup- which intracellular signaling pathways do these port F-actin nucleation on neurexins. J Biol Chem 276: 47869–47876. proteins engage? Addressing these questions Biederer T,Sara Y,Mozhayeva M, Atasoy D, Liu X, Kavalali ET, will integrate our understanding of how synap- Su¨dhof TC. 2002. SynCAM, a synaptic adhesion molecule tic cell adhesion molecules guide synapse devel- that drives synapse assembly. Science 297: 1525–1531. opment and the plasticity of mature synapses Boucard AA, Chubykin AA, Comoletti D, Taylor P, Su¨dhof TC. 2005. A splice code for trans-synaptic cell adhesion and how altered synaptic cell adhesion can un- mediated by binding of neuroligin 1 to a- and b-neurex- derlie brain disorders. ins. Neuron 48: 229–236.

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Synaptic Cell Adhesion

Markus Missler, Thomas C. Südhof and Thomas Biederer

Cold Spring Harb Perspect Biol published online January 25, 2012

Subject Collection The Synapse

Studying in Single Dendritic Synaptic Vesicle Endocytosis Spines Yasunori Saheki and Pietro De Camilli Ryohei Yasuda Synaptic Vesicle Pools and Dynamics Short-Term Presynaptic Plasticity AbdulRasheed A. Alabi and Richard W. Tsien Wade G. Regehr Synapses and Memory Storage NMDA Receptor-Dependent Long-Term Mark Mayford, Steven A. Siegelbaum and Eric R. Potentiation and Long-Term Depression Kandel (LTP/LTD) Christian Lüscher and Robert C. Malenka Synapses and Alzheimer's Disease Ultrastructure of Synapses in the Mammalian Morgan Sheng, Bernardo L. Sabatini and Thomas Brain C. Südhof Kristen M. Harris and Richard J. Weinberg Synaptic Cell Adhesion Calcium Signaling in Dendritic Spines Markus Missler, Thomas C. Südhof and Thomas Michael J. Higley and Bernardo L. Sabatini Biederer Synaptic Dysfunction in Neurodevelopmental Synaptic Neurotransmitter-Gated Receptors Disorders Associated with Autism and Intellectual Trevor G. Smart and Pierre Paoletti Disabilities Huda Y. Zoghbi and Mark F. Bear The Postsynaptic Organization of Synapses Synaptic Vesicle Exocytosis Morgan Sheng and Eunjoon Kim Thomas C. Südhof and Josep Rizo Presynaptic LTP and LTD of Excitatory and Vesicular and Plasma Membrane Transporters for Inhibitory Synapses Pablo E. Castillo Randy D. Blakely and Robert H. Edwards

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