Synaptic adhesion molecules and PSD-95

Progress in Neurobiology 84 (2008) 263–283 www.elsevier.com/locate/pneurobio

Synaptic adhesion molecules and PSD-95 Kihoon Han, Eunjoon Kim * National Creative Research Initiative Center for Synaptogenesis and Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Kuseong-dong, Yuseong-ku, Daejeon 305-701, Republic of Korea Received 2 July 2007; received in revised form 31 August 2007; accepted 26 October 2007

Abstract Synaptic adhesion molecules are known to participate in various steps of synapse development including initial contacts between dendrites and axons, formation of early synapses, and their maturation and plastic changes. Notably, a significant subset of synaptic adhesion molecules associates with synaptic scaffolding proteins, suggesting that they may act in concert to couple trans-synaptic adhesion to molecular organization of synaptic proteins. Here, we describe an emerging group of synaptic adhesion molecules that directly interact with the abundant postsynaptic scaffold PSD-95, which include neuroligins, NGLs, SALMs, and ADAM22, and discuss how these proteins and PSD-95 act together to regulate synaptic development. PSD-95 may be one of the central organizers of synaptic adhesion that recruits diverse proteins to sites of synaptic adhesion, promotes trans-synaptic signaling, and couples neuronal activity with changes in synaptic adhesion. # 2007 Elsevier Ltd. All rights reserved. Keywords: PSD-95; Neuroligin; Neurexin; Netrin-G; NGL; SALM; ADAM22; Synapse

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PSD-95. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PSD-95-interacting adhesion molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Neurexins and neuroligins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Netrin-Gs and NGLs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. SALMs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. LGI1 and ADAM22 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concerted actions of PSD-95 and PSD-95-interacting adhesion molecules . . . . 4.1. Synaptic localization of adhesion molecules and PSD-95 . . . . . . . . . . . 4.2. Functional modulation of adhesion molecules by PSD-95 . . . . . . . . . . . 4.3. Regulation of postsynaptic receptors by adhesion molecules and PSD-95 4.4. Regulation of the excitatory–inhibitory balance . . . . . . . . . . . . . . . . . . 4.5. Presynaptic induction and retrograde modulation . . . . . . . . . . . . . . . . . 4.6. Activity-dependent regulation of synaptic adhesion. . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: ADAM, a disintegrin and metalloprotease; ADPEAF, autosomal dominant partial epilepsy with auditory features; AKAP, a kinase-anchoring protein; AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; EPSC, excitatory postsynaptic current; GABA, gamma-aminobutyric acid; GK, guanylate kinase; GKAP, guanylate kinase-associated protein; GPI, glycosylphosphatidylinositol; LGI, leucine-rich, glioma inactivated; Lrfn, leucine-rich repeat and fibronectin III domain-containing; LRR, leucine-rich repeat; LTD, long-term depression; LTP, long-term potentiation; NGL, netrin-G ligand; NMDA, N-methyl-Daspartic acid; NO, nitric oxide; NOS, nitric oxide synthase; PDZ, PSD-95/Dlg/ZO-1; PSD, postsynaptic density; PSD-95, postsynaptic density-95; SALM, synaptic adhesion-like molecule; SH3, Src homology 3; TARP, transmembrane AMPA receptor regulatory protein. * Corresponding author. Tel.: +82 42 869 2633; fax: +82 42 869 8127. E-mail address: [email protected] (E. Kim). 0301-0082/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2007.10.011

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1. Introduction Synapse formation involves various molecular and cellular processes including contact between presynaptic and postsynaptic structures, formation of early synapses, and stabilization and differentiation of early synapses into mature synapses. Synaptic adhesion molecules are known to play pivotal roles in each of these processes, and some synaptic adhesion molecules likely regulate more than a single step of these developments. At the molecular level, the extracellular domains of synaptic adhesion molecules participate in trans-synaptic adhesion, while their cytoplasmic domains on the pre- and postsynaptic sides associate with intracellular proteins to couple synaptic adhesion to molecular organization of multiprotein complexes. Examples of such adhesion molecules include neuroligin, neurexin, SynCAM, NCAM, N-cadherin, protocadherin, Eph receptors, ephrin, and NGL. The functions of these molecules, along with the cell biological principles of synapse development, have recently been summarized in excellent reviews (Akins and Biederer, 2006; Craig et al., 2006; Craig and Kang, 2007; Dalva et al., 2007; Dean and Dresbach, 2006; Gerrow and El-Husseini, 2006; Ichtchenko et al., 1996; Li and Sheng, 2003; McAllister, 2007; Piechotta et al., 2006; Scheiffele, 2003; Waites et al., 2005; Washbourne et al., 2004; Yamagata et al., 2003). Here, we focus on an emerging group of synaptic adhesion molecules that directly interact, through their cytoplasmic domains, with PSD-95, an abundant postsynaptic scaffolding protein regulating the formation, function, and plasticity of excitatory synapses. Electron microscopic studies have revealed that PSD-95 is localized very close to the postsynaptic membrane (Petersen et al., 2003; Valtschanoff and Weinberg, 2001), suggesting that PSD-95 is localized in an ideal position to link extrasynaptic adhesion to cytoplasmic protein organization. Synaptic adhesion molecules that directly interact with PSD-95 include neuroligins, NGLs, SALMs, and ADAM22. In this review, we will summarize these adhesion molecules and describe aspects of PSD-95 that are relevant to synaptic adhesion. Another aim of this paper is to discuss possible functions of the interaction between PSD-95 and the adhesion molecules, taking into account the known functions of PSD-95. 2. PSD-95 PSD-95 (also known as SAP90) is a synaptic scaffolding protein with multiple protein–protein interaction domains that is enriched in the postsynaptic density (PSD), an electron-dense specialization of postsynaptic membrane that contains macromolecular protein complexes (Cho et al., 1992; Funke et al., 2004; Kim and Sheng, 2004; Kistner et al., 1993; Sheng and Hoogenraad, 2007). Recent studies indicate that PSD-95 is one of the most abundant proteins in the PSD (Chen et al., 2005; Cheng et al., 2006; Sheng and Hoogenraad, 2007; Sugiyama et al., 2005). Because the structural and functional characteristics of PSD-95 have recently been summarized (Funke et al., 2004; Kim and Sheng, 2004; Sheng and Hoogenraad, 2007), we

will mainly focus on the characteristics of PSD-95 that are more relevant to its functional regulation of synaptic adhesion. PSD-95 belongs to the PSD-95 family that has four known members: PSD-95/SAP90, PSD-93/chapsyn-110, SAP97, and SAP102. PSD-95 family proteins share similar domain structures. PSD-95 contains, from the N-terminus, three PDZ domains, an SH3 domain, and a GK domain (Fig. 1A). In addition, alternative splicing generates splice variants of PSD95, PSD-93, and SAP97 (known as b splice variants for PSD-95 and SAP97) that contain an L27 domain at the N-terminus (Chetkovich et al., 2002; Parker et al., 2004); this domain mediates protein multimerization and regulates excitatory synaptic strength (Nakagawa et al., 2004; Schluter et al., 2006). The PDZ domain is a 90-residue-long module that binds short peptide motifs at the extreme C-termini of other proteins. PDZ domains are found in a large number of proteins (ca. 400 proteins in the human genome), where tandem arrangements of PDZ domains are commonly observed. PDZ domains fall mainly into two classes based on the sequence of their peptide ligands. The class I ligand has a serine or threonine residue at the 2 position, whereas the class II ligand contains a hydrophobic residue at the same position (Hung and Sheng, 2002). The three PDZ domains of PSD-95, which belong to class I, interact with various neuronal proteins including membrane and signaling proteins. The SH3 and GK domains of PSD-95, contained in the second half of the protein, also participate in protein interactions (Kim and Sheng, 2004). Of note, the SH3 domain of PSD-95 interacts with the GK domain in an intramolecular fashion (McGee and Bredt, 1999; Shin et al., 2000), which is thought to contribute to the structural stabilization of PSD-95. This interaction, when it occurs in an intermolecular fashion, may contribute a tail-to-tail multimerization of PSD-95 (McGee et al., 2001; Tavares et al., 2001). PSD-95 can also be multimerized in a head-to-head fashion through the interaction of N-terminal segments containing two critical cysteine residues (Christopherson et al., 2003; Hsueh et al., 1997; Hsueh and Sheng, 1999). PSD-95 has diverse synaptic functions. One such function is to interact with membrane proteins and regulate their synaptic localization. PSD-95 seems to stabilize interacting membrane proteins at synapses by suppressing their lateral diffusion or internalization (Bats et al., 2007; Prybylowski et al., 2005; Roche et al., 2001). In addition to its role in protein trafficking, PSD-95 can regulate the functional properties of interacting membrane proteins, as shown by PSD-95-dependent changes in the gating of NMDA receptors (Lin et al., 2006), and the singlechannel conductance of the inward rectifier potassium channel Kir2.3 (Nehring et al., 2000). PSD-95 is an important regulator of synaptic strength and plasticity. PSD-95 overexpression in cultured neurons increases synaptic AMPA receptor clustering and currents (El-Husseini et al., 2000). In brain slices, PSD-95 overexpression increases the frequency of miniature excitatory postsynaptic currents (mEPSCs), enhances AMPA, but not NMDA, receptormediated EPSCs, promotes synaptic delivery of GluR1containing AMPA receptors, occludes long-term potentiation

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Fig. 1. Schematic diagram of PSD-95, PSD-95-interacting adhesion molecules, and their ligands. (A) Domain structure of PSD-95. Alternative splicing at the Nterminal region introduces the L27 domain in the b splice variant of PSD-95. L27, LIN-2, -7 domain; PDZ, PSD-95/Dlg/ZO-1 domain; SH3, Src homology 3 domain; GK, guanylate kinase-like domain. (B) Domain structure of PSD-95-interacting adhesion molecules, and their ligands. Both a-neurexin and b-neurexin bind neuroligins. SALM2 does not have known ligands. AchE, acetylcholinesterase-homologous domain; CT, LRR C-terminal domain; CR, cysteine-rich region; DI, disintegrin domain; EGF, epidermal growth-factor-like domain; EPTPs, epitempin repeats; FNIII, fibronectin type III domain; Glyc, O-glycosylation region; GPI, glycosylphosphatidylinositol anchor; Ig, immunoglobulin domain; LEGF, laminin-type EGF-like domain; LN, laminin N-terminal domain; LNS, laminin, neurexin, sex-hormone-binding protein domain; LRRs, leucine-rich repeats; MP, metalloprotease domain; NT, LRR N-terminal domain; bN, b-neurexin specific sequence; PB, PDZ-binding motif; PRO, prodomain; TM, transmembrane region.

(LTP), enhances long-term depression (LTD), and occludes experience-driven synaptic AMPA receptor delivery (Beique and Andrade, 2003; Ehrlich and Malinow, 2004; Schnell et al., 2002; Stein et al., 2003). PSD-95 overexpression in slices also retrogradely increases presynaptic release probability through neuroligins (Futai et al., 2007). Conversely, acute knockdown of PSD-95 in brain slices by RNA interference reduces synaptic AMPA, but not NMDA, receptor currents (Elias et al., 2006; Nakagawa et al., 2004; Schluter et al., 2006), although reductions in both AMPA and NMDA receptor currents are observed in other studies (Ehrlich et al., 2007; Futai et al.,

2007). In contrast to these significant results from in vitro experiments, transgenic mice with targeted truncation of PSD95 show normal excitatory synaptic structure and function (Migaud et al., 1998), suggesting that other PSD-95 family members may be compensating the effects of PSD-95 deletion. Indeed, mice deficient of both PSD-95 and PSD-93 show markedly reduced AMPA receptor-mediated synaptic currents (Elias et al., 2006). Supporting PSD-95 involvement in synaptic plasticity, LTP is enhanced in both PSD-95 null mice and in mice with targeted PSD-95 truncation (Beique et al., 2006; Migaud et al., 1998). Of note, acute PSD-95 knockdown in

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brain slices does not block induction and early expression of LTP, but suppresses morphological maturation of dendritic spines during development and LTP (Ehrlich et al., 2007). How might PSD-95 regulate synaptic strength and plasticity? An important mediator is stargazin, a member of the TARP (for transmembrane AMPA receptor regulatory protein) family of AMPA receptor auxiliary subunits (Derkach et al., 2007; Nicoll et al., 2006). Stargazin regulates the maturation, trafficking, synaptic stability, and biophysical properties of AMPA receptors (Nicoll et al., 2006; Ziff, 2007). Stargazin traffics AMPA receptors to synapses by two distinct mechanisms: enhancement in surface expression of AMPA receptors by stargazin, and synaptic localization of the AMPA receptor–stargazin complex by the PDZ interaction of the stargazin C-terminus with PSD-95 (Chen et al., 2000). Stargazin is phosphorylated on a cluster of cytoplasmic serine residues, and this phosphorylation regulates bidirectional synaptic plasticity (Tomita et al., 2005). In addition to the AMPA receptor–stargazin complex, PSD95 interacts with the NR2 subunits of NMDA receptors (Kornau et al., 1997; Niethammer et al., 1996). Synaptic localization of NMDA receptors, however, is less sensitive to overexpression, or knockdown of PSD-95, compared to AMPA receptors (ElHusseini et al., 2000; Elias et al., 2006; Nakagawa et al., 2004). Rather, PSD-95 seems to regulate functional aspects of NMDA receptors (Sheng and Kim, 2002), although PSD-95 binding suppresses internalization of NR2B-containing NMDA receptors (Roche et al., 2001). For instance, PSD-95 binds Fyn, a Src family tyrosine kinase, and promotes Fyn-mediated tyrosine phosphorylation of the NR2A subunit of NMDA receptors (Tezuka et al., 1999). The functions of the interaction between PSD-95 and NMDA receptors remain, however, largely unknown (Wenthold et al., 2003). PSD-95 interacts with a variety of synaptic signaling proteins (Funke et al., 2004; Kim and Sheng, 2004; Sheng and Hoogenraad, 2007). For instance, PSD-95 interacts directly with neuronal nitric oxide synthase (nNOS) and kalirin-7 (a guanine nucleotide exchange factor for Rac1). PSD-95 often indirectly associates with signaling molecules through other scaffolds (i.e., GKAP and Shank) or signaling adaptors (i.e., AKAP79/150). It is believed that PSD-95 either promotes synaptic localization of associated signaling molecules, or organizes synaptic signaling pathways by bringing them into close proximity. For instance, PSD-95 forms a ternary complex with both NMDA receptors and nNOS, promoting functional coupling between NMDA receptor activation and NO production by calcium-activated nNOS (Christopherson et al., 1999; Sattler et al., 1999). In another example, PSD-95 interacts with both kalirin-7 and IRSp53, a downstream effector of Rac1, possibly constituting the signaling pathway connecting kalirin7, Rac1, and IRSp53 around PSD-95 (Choi et al., 2005; Penzes et al., 2001). PSD-95 is an early protein detected at nascent synapses (Bresler et al., 2001; Friedman et al., 2000; Okabe et al., 2001). Although PSD-95 is a relatively stable synaptic protein, PSD95 undergoes continual cycling into and out of synapses (Gray et al., 2006; Inoue and Okabe, 2003; Marrs et al., 2001; Okabe

et al., 1999). Synaptic localization of PSD-95 is regulated by neuronal activities and mechanisms including protein palmitoylation and phosphorylation. Blockade of NMDA receptors suppresses generation of synaptic PSD-95 clusters, reducing the total number, whereas AMPA receptor blockade inhibits both the generation and elimination of PSD-95 clusters, without affecting the total cluster number (Okabe et al., 1999). Eye opening rapidly translocates PSD-95 to synapses in visual cortical neurons (Yoshii et al., 2003). NMDA receptor activation delivers PSD-95 to dendrites and synapses through the BDNF-TrkB-PI3K-Akt pathway (Yoshii and ConstantinePaton, 2007). PSD-95 is palmitoylated on two N-terminal cysteine residues (El-Husseini Ael and Bredt, 2002). Blocking of PSD-95 palmitoylation disperses synaptic PSD-95 clustering and reduces the number of synaptic AMPA receptors (ElHusseini Ael et al., 2002). In addition, glutamate-induced AMPA receptor endocytosis requires depalmitoylation of PSD95 (El-Husseini Ael et al., 2002). Cyclin-dependent kinase 5 (cdk5) phosphorylates the N-terminal region of PSD-95 and negatively regulates synaptic clustering of PSD-95, possibly by reducing multimerization of the protein (Morabito et al., 2004). Expression and degradation of PSD-95 are regulated by diverse molecular mechanisms. Expression levels of PSD-95 are increased during postnatal brain development (Sans et al., 2000). PSD-95 transcription is promoted by neuregulin-1, a ligand for ErbB receptor tyrosine kinases. ErbB binding to neuregulin-1 (a transmembrane isoform) at the presynaptic nerve terminal induces cleavage and translocation of the intracellular domain of neuregulin-1 to the nucleus to promote PSD-95 expression (Bao et al., 2004). Estrogen facilitates rapid PSD-95 translation through the Akt pathway (Akama and McEwen, 2003). Neuronal activity regulates the turnover and molecular composition of synaptic proteins through the ubiquitin-proteasome pathway (Bingol and Schuman, 2005; Yi and Ehlers, 2007). NMDA receptor activation induces rapid degradation of PSD-95 through the ubiquitin-proteasome pathway (Colledge et al., 2003). In addition, AMPA receptor activation induces PSD-95 degradation through the proteasome pathway, although PSD-95 polyubiquitination is not detected (Bingol and Schuman, 2004). Activity-induced serum-inducible kinase (SNK) phosphorylates SPAR, an actin-regulatory protein with GTPase-activating protein activity for Rap small GTPases, and induces degradation of SPAR, removal of PSD95 clusters, and selective loss of mature dendritic spines (Pak and Sheng, 2003). PSD-95 appears to be associated with the pathophysiology of mental retardation and addiction. The fragile X mental retardation protein FMRP binds to PSD-95 mRNAs, which are detected in dendrites, and regulates the stability and metabotropic glutamate receptor-dependent translation of these molecules (Muddashetty et al., 2007; Todd et al., 2003; Zalfa et al., 2007). Implicating involvement of PSD-95 in addiction (Roche, 2004), PSD-95 is downregulated in the striatum of three different addiction model mice and chronically cocainetreated mice (Yao et al., 2004). In addition, mice with targeted truncation of PSD-95 show enhanced frontocortico-accumbal LTP and heightened locomotor responses to acute cocaine, but

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absence of cocaine-induced behavioral plasticity (Yao et al., 2004). PSD-95 interacts with dopamine D1 receptors and downstream signaling, suggesting that this mechanism may explain the enhanced behavioral responses to psychostimulants in PSD-95-deficient mice (Zhang et al., 2007). 3. PSD-95-interacting adhesion molecules 3.1. Neurexins and neuroligins Neurexin is a type I transmembrane protein, first identified as a receptor of a-latrotoxin, a component of the venom of black widow spider, that induces massive neurotransmitter release (Sudhof, 2001; Ushkaryov et al., 1992). Neurexin is encoded by three genes (neurexin 1, neurexin 2, and neurexin 3). Each neurexin gene contains two promoters, which generate long a-neurexins and short b-neurexins. The extracellular region of a-neurexin has six LNS (for laminin, neurexin, sex hormone-binding protein) domains with three EGF-like sequences, while b-neurexin has a b-neurexin-specific sequence followed by a single LNS domain (Fig. 1B). Both a- and b-neurexin have N- and O-glycosylation sites, and their cytoplasmic regions end with a class II PDZ-binding motif. The a-neurexin and b-neurexin have five and two alternative splice sites, respectively, and could potentially generate more than a thousand isoforms (Missler and Sudhof, 1998; Rowen et al., 2002; Tabuchi and Sudhof, 2002; Ullrich et al., 1995). Neuroligin 1 was first identified as a ligand of b-neurexin (Ichtchenko et al., 1995). There are four known neuroligin genes in rodents (neuroligins 1, 2, 3, and 4) and five in humans (neuroligins 1, 2, 3, 4, and 4Y; 4Y is present in the Y

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chromosome) (Bolliger et al., 2001; Ichtchenko et al., 1996). Neuroligin contains a catalytically inactive cholinesterase-like domain in its extracellular region, followed by a single transmembrane domain, and a cytoplasmic domain that ends with a class I C-terminal PDZ-binding motif (Fig. 1B). Neuroligin 1 has N- and O-glycosylation sites on its extracelluar region. O-glycosylation sites are clustered in a membraneproximal region, similar to neurexins (Fig. 1B) (Ichtchenko et al., 1995). There are two alternative splice sites (A and B) in the extracellular region of the neuroligins (Ichtchenko et al., 1995; Ichtchenko et al., 1996), and these are used to regulate neurexin binding and synaptic localization (see below). Neurexins are expressed mainly in the brain (Ushkaryov et al., 1992). Immunostaining detects endogenous neurexins in axonal growth cones and presynaptic sites (Dean et al., 2003). Functional analysis with a-neurexin knockout (KO) mice, however, has found a decrease in postsynaptic NMDA receptor activity, suggesting that neurexins may have additional postsynaptic functions (Kattenstroth et al., 2004). Indeed, a recent study reports that neurexins are ultrastructurally located at both pre- and postsynaptic sites (Taniguchi et al., 2007). Neuroligin 1 is expressed mainly in the brain, while other neuroligins have more diverse tissue distribution patterns (Bolliger et al., 2001; Philibert et al., 2000). In neurons, electron microscopy detects endogenous neuroligin 1 on the postsynaptic side of excitatory synapses (Song et al., 1999), whereas neuroligin 2 is located mainly in inhibitory synapses (Chih et al., 2005; Graf et al., 2004; Levinson et al., 2005; Varoqueaux et al., 2004). Neurexins and neuroligins form a trans-synaptic complex in a Ca2+-dependent manner (Ichtchenko et al., 1995; Nguyen and Sudhof, 1997) (Fig. 2). In addition to the long-known

Fig. 2. Interaction of PSD-95-interacting adhesion molecules with their specific extracellular ligands and cytoplasmic scaffolds at synapses. Interaction of adhesion molecules with extracellular ligands and cytoplasmic scaffolds are indicated by bidirectional arrows (yellow thick arrows for adhesions, and black thin arrows for cytoplasmic interactions). Specific domains involved in adhesions are described in the text. The presynaptic ligand of SALM2 is unknown. LGI1 is a secreted protein. Domains in PSD-95 and CASK involved in adhesion molecule binding are indicated by brackets. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of the article.)

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interaction between b-neurexins and neuroligins, a recent study has revealed that neuroligins can bind a-neurexins (Boucard et al., 2005) (Fig. 2). Interestingly, N-glycosylation of the extracellular splice insert B of neuroligin 1 negatively regulates a-neurexin binding. Neuroligins without the B splice insert therefore interact with both a-neurexin and b-neurexin, whether the A splice insert is present or not (Boucard et al., 2005). Neuroligin 1 that binds only b-neurexins promotes synapse formation, whereas neuroligin 1 that binds both a- and b-neurexins enhances synapse expansion (Boucard et al., 2005). Neuroligin splicing also regulates synaptic localization in addition to neurexin binding (Chih et al., 2006). The A splice insert drives neuroligin 1 to inhibitory synapses, whereas insert B, which is dominant to insert A, localizes neuroligin 1 to excitatory synapses. A neuroligin 1 variant that lacks both A and B inserts localizes to both excitatory and inhibitory synapses (Chih et al., 2006). This could explain, at least in part, why endogenous neuroligin 2, which does not have splice site B, mainly localizes to inhibitory synapses. Conversely, alternative splicing in neurexins also regulates neuroligin binding. The splice insert of neurexin at splice site 4 inhibits neurexin adhesion to neuroligins with splice insert B, with the degree of inhibition depending on the experimental conditions (Boucard et al., 2005; Chih et al., 2006; Graf et al., 2006). It is therefore likely that b-neurexins without insert 4, and neuroligins with insert B, promote excitatory synaptic differentiation, while b-neurexins with insert 4 and neuroligins without insert B localize to and promote inhibitory synaptic differentiation (Craig and Kang, 2007). The trans-synaptic adhesion between neuroligins and neurexins induces both pre-and postsynaptic differentiation. In support of a role for neuroligin in presynaptic differentiation, neuroligin-expressing nonneural cells cocultured with neurons induce morphological and functional differentiation of excitatory and inhibitory presynaptic structures in contacting axons (Biederer and Scheiffele, 2007; Graf et al., 2004; Scheiffele et al., 2000). Coexpression of AMPA or NMDA receptors in heterologous cells in coculture experiments reconstitutes functional hemi-synapses that are similar to regular neuronneuron synapses (Fu et al., 2003; Sara et al., 2005). Neuroligin 2, but not neuroligin 1, reconstitutes functional GABA synapses in coculture assays, when coexpressed with GABAA receptors (Dong et al., 2007). Neuroligin alone is sufficient to induce presynaptic differentiation, because neuroligin-coated beads have the same presynapse-inducing effects (Dean et al., 2003). Neuroligin-induced presynaptic differentiation in coculture experiments is blocked by soluble b-neurexin (Levinson et al., 2005; Scheiffele et al., 2000). In addition, direct clustering of neurexin on axons is sufficient to recruit presynaptic proteins (Dean et al., 2003). Multimerization of neuroligin is required for its presynaptic induction (Comoletti et al., 2003; Dean et al., 2003), suggesting that neurexin clustering induced by multimeric neuroligins initiates presynaptic differentiation. Synapse formation by neurexins and neuroligins occurs in a bidirectional manner; b-neurexin induces postsynaptic differentiation through neuroligins (Graf et al., 2004; Nam and Chen,

2005). b-Neurexin expressed in nonneural cells, or coated on beads, induces dendritic clustering of both excitatory and inhibitory postsynaptic proteins including PSD-95, gephyrin (an inhibitory synaptic scaffold), GABAA receptors, and NMDA receptors, but not AMPA receptors, in contacting dendrites. Neuroligin aggregation alone is sufficient to induce postsynaptic protein clustering (Graf et al., 2004). It is of note that neuroligin 2 coclusters with both PSD-95 and gephyrin, whereas neuroligin 1 recruits only PSD-95, consistent with the endogenous distributions of the neuroligins (Graf et al., 2004). Thus, the neurexin-neuroligin complex bidirectionally regulates excitatory and inhibitory synapse formation. The types and expression levels of neuroligins in a single neuron determine the number and function of both excitatory and inhibitory synapses. Overexpression of neuroligin 1 in cultured neurons increases the number of dendritic spines, postsynaptic protein clusters (containing PSD-95 and NMDA receptors), and presynaptic inputs (Chih et al., 2005; Levinson et al., 2005; Prange et al., 2004). In agreement with the coculture results, overexpression of any single neuroligin isoform (neuroligin 1, 2, or 3) increases the number of both excitatory and inhibitory presynaptic inputs on dendrites, although neuroligin 2 has a stronger effect on inhibitory synapse formation (Chih et al., 2005; Levinson et al., 2005). Knockdown of single or multiple neuroligins results in decreases in the number of dendritic spines and clusters of both excitatory and inhibitory synaptic proteins (Chih et al., 2005). Functional analyses indicate, however, that neuroligin knockdown induces a larger decrease in the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) than those in mEPSCs, suggesting that inhibitory synapses are functionally more sensitive to neuroligin decrease (Chih et al., 2005). The cytoplasmic regions of neurexins and neuroligins, which interact with various cytoplasmic proteins (mostly scaffolds), contribute to their synaptogenic activities. The Cterminal class II PDZ-binding motifs of neurexins interact with PDZ proteins including CASK, Mint, and syntenin (Biederer and Sudhof, 2000; Grootjans et al., 2000; Hata et al., 1996). The cytoplasmic regions of neurexins also interact with synaptotagmin, a presynaptic vesicle protein (Hata et al., 1993; Perin, 1994). These interactions may promote the recruitment of presynaptic release machineries to the site of neurexinneuroligin binding. In support of this, direct clustering of a mutant neurexin that lacks the cytoplasmic region containing the PDZ-binding motif does not induce presynaptic differentiation (Dean et al., 2003). The C-terminal class I PDZbinding motif of neuroligins interacts with PSD-95, S-SCAM, and several other PDZ proteins (Hirao et al., 1998; Iida et al., 2004; Irie et al., 1997; Meyer et al., 2004). PSD-95 and other PDZ proteins may bring diverse postsynaptic proteins to the neurexin-neurolgin complex. Once recruited to synapses, PSD-95 and S-SCAM may conversely promote synaptic targeting and clustering of neuroligins (Iida et al., 2004; Prange et al., 2004). PSD-95 concentrates neuroligin 1 at excitatory synapses, and translocates neuroligin 2 from inhibitory to excitatory synapses,

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increasing the ratio of excitatory-to-inhibitory synapses (Graf et al., 2004; Levinson and El-Husseini, 2005; Prange et al., 2004). Little is known about the proteins that interact with neuroligin 2 at inhibitory synapses, although S-SCAM, which interacts with neuroligin 2 and partially distributes to inhibitory synapses, is a candidate (Sumita et al., 2007). Although in vitro experiments strongly suggest that neurexins and neuroligins are important for synapse formation, results from in vivo mouse models lead to a different conclusion. a-Neurexin triple KO mice, which have intact b-neurexin expression, have breathing problems and die shortly after birth (Missler et al., 2003). Interestingly, the density of type II symmetric synapses (probably inhibitory), but not type I asymmetric (probably excitatory) synapses, is moderately reduced in the brainstem of newborn and surviving adult KO mice (Dudanova et al., 2007; Missler et al., 2003). In contrast, a-neurexin triple KO mice show marked decreased spontaneous and evoked neurotransmitter releases at both excitatory and inhibitory synapses, caused by reduced function of N-type and P/Q-type Ca2+ channels (Missler et al., 2003; Zhang et al., 2005b). These phenotypes are rescued by a-neurexin 1 but not by b-neurexin 1, suggesting that the large extracellular region of a-neurexin 1 is important (Zhang et al., 2005b). Neuroligin 1–3 triple KO mice have normal brain cytoarchitecture at birth, but die within 24 h, possibly due to a respiratory problem (Varoqueaux et al., 2006). In this respect, the phenotype is similar to that of a-neurexin KO mice. Surprisingly, the numbers and morphologies of hippocampal and neocortical synapses in neuroligin triple KO mice are indistinguishable from those of wild-type mice. Even in the brainstem where the neural networks are almost mature at birth, synapse number is unaffected, although small changes are observed in the ratio of VIAAT to vGlut1 (inhibitory and excitatory presynaptic markers, respectively) and the number of GABAA receptors. Importantly, significant impairments are observed in GABAergic/glycinergic and glutamatergic transmission in the respiratory centers of the brainstem. Thus, synaptic maturation and functions, rather than initial synapse formation, constitute the main difference from wild-type in neuroligin triple KO mice. Consistent with this conclusion, a recent study shows that overexpression of neuroligin 1 in cultured neurons increases morphological synapse number and the ratio of NMDA to AMPA receptor EPSCs (Chubykin et al., 2007). Importantly, this enhancement is abolished by chronic blockade of NMDA receptors and CaM kinase II, an abundant postsynaptic protein acting downstream of NMDA receptors. Similarly, neuroligin 2 increases the number and function of inhibitory synapses in a manner requiring general synaptic activity. These results suggest that neuroligins may regulate the stabilization and maturation of synapses rather than their initial formation. The functional association between neuroligin 1 and NMDA receptors may depend on PSD-95, which binds both neuroligin 1 and NMDA receptors. Recent genetic studies in human patients have revealed that mutations in neuroligin 3 and neuroligin 4 genes are associated with X-linked mental retardation and autism (Jamain et al.,

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2003; Laumonnier et al., 2004; Yan et al., 2005). In vitro experiments show that the mutations found in human patients impair proper membrane targeting of neuroligins, and thus reduce the synaptogenic activities of these proteins (Chih et al., 2004; Chubykin et al., 2005; Comoletti et al., 2004). Neurexins have been suggested as candidate autism risk loci (Szatmari et al., 2007). These results highlight the importance of neuroligins and neurexins in human brain dysfunctions, although it is not yet clear whether neuroligin and neurexin genes are major causative genes for mental retardation or autism (Blasi et al., 2006; Gauthier et al., 2005; Vincent et al., 2004). In addition, these results suggest the possibility that neurexin and neuroligin KO mice may be appropriate animal models for the study of mental retardation and autism (Varoqueaux et al., 2006). 3.2. Netrin-Gs and NGLs Netrin-Gs (also called laminets) were identified as molecules related to laminins and UNC-6/netrins, which are secreted extracellular matrix glycoproteins and axon guidance molecules, respectively (Nakashiba et al., 2000; Nakashiba et al., 2002; Yin et al., 2002). There are two known netrin-Gs: netrin-G1 and netrin-G2. Although structurally related, netrinGs differ from netrins in several ways. Netrin-Gs are not secreted but are rather tethered to the plasma membrane through a glycosylphosphatidylinositol (GPI) anchor (Nakashiba et al., 2000; Nakashiba et al., 2002). Netrin-Gs do not interact with known netrin receptors including DCC and UNC5. Netrin-G1 does not induce neurite outgrowth of cerebellar plate explant, in contrast to netrin-1 (Nakashiba et al., 2000; Nakashiba et al., 2002). Netrin-Gs contain a laminin N-terminal domain (also called domain VI), three laminin-type EGF-like domains (domains V1 to V-3), a non-laminin-type EGF-like domain, and a Cterminal GPI-linkage site (Nakashiba et al., 2000, 2002; Yin et al., 2002) (Fig. 1B). Multiple splice variants of netrin-G1 and netrin-G2 exist, with the splice sites occurring mainly in EGFlike domains, suggesting that the splicing may regulate netrinG functions (Meerabux et al., 2005; Nakashiba et al., 2000, 2002; Yin et al., 2002). Northern blot analysis indicates that mouse netrin-G1 and netrin-G2 mRNAs are predominantly expressed in brain, with weak expression of netrin-G2 in other tissues including heart, lung, and kidney (Nakashiba et al., 2000; Nakashiba et al., 2002; Yin et al., 2002). Expression of splice variants of human netrin-G1 mRNAs is regulated in a development- and tissuedependent manner (Meerabux et al., 2005). In situ hybridization indicates that netrin-G1 and netrin-G2 mRNAs exhibit mainly nonoverlapping expression patterns in brain regions (Nakashiba et al., 2000, 2002; Yin et al., 2002). This suggests that netrin-G1 and netrin-G2 may regulate the formation of specific neural circuits during brain development. At the protein level, netrin-G1 proteins are expressed in the dorsal thalamus and detected on thalamocortical axons (Nakashiba et al., 2002). During embryonic brain development, thalamocortical axons migrate through striatum to cerebral

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cortex. This specific trajectory of thalamocortical axons may require defined extracellular ligands that mediate chemoattraction and chemorepulsion (Braisted et al., 1999). NGL-1 (netrin-G ligand-1) was identified as a specific ligand of netrinG1 and is highly expressed in target regions of thalamocortical axons, including striatum and cerebral cortex (Lin et al., 2003). NGL-1, when coated on culture plates, promotes neurite outgrowth of cultured thalamic neurons. Injection of soluble NGL-1 into the neural tube of chick embryos prevents the growth of thalamofugal axons, possibly by competing with endogenous NGL-1 for netrin-G1 binding (Lin et al., 2003). These results suggest that NGL-1 regulates the outgrowth and migration of thalamocortical axons during embryonic brain development. There are two additional members of the NGL family: NGL2 (also known as LRRC4) and NGL-3 (Kim et al., 2006; Zhang et al., 2005a). Invertebrate orthologs of NGL have not been found. NGL family proteins share a similar domain organization consisting of nine leucine-rich repeats (LRRs) flanked by cysteine-rich LRR N- and C-terminal (LRRNT and LRRCT) domains, and an immunoglobulin (Ig) domain in the extracellular region (Fig. 1B). These domains are followed by a single transmembrane domain and a cytoplasmic region that ends with a C-terminal class I PDZ-binding motif (Fig. 1B). Sequence alignment of NGLs indicates that their extracellular regions are similar to each other, whereas the cytoplasmic regions are minimally conserved except for the Cterminal PDZ-binding motifs, suggesting that different NGLs may have distinct functions. NGLs bind to netrin-Gs in an isoform-specific manner (Kim et al., 2006; Lin et al., 2003). NGL-1 selectively interacts with netrin-G1 but not with netrin-G2. Similarly, NGL-2 binds to netrin-G2 but not to netrin-G1. NGL-3 does not bind to either netrin-G1 or netrin-G2, suggesting that NGL-3 may have a novel ligand. The LRR domain of NGL-1 mediate NGL-1 adhesion to netrin-G1 (Lin et al., 2003), but the NGL-binding domain of netrin-G1 has not been identified. NGLs adhere to netrin-Gs in a Ca2+-independent manner (Kim et al., 2006). It is unknown whether the extensive alternative splicing of netrinGs regulates NGL binding. NGLs are modified by Nglycosylation (Kim et al., 2006), which may regulate netrinG binding. Northern blot analysis indicates that mRNAs of NGLs are expressed mainly in brain, while NGL-1 and NGL-3 mRNAs are additionally expressed at low levels in liver and heart, respectively (Kim et al., 2006; Lin et al., 2003; Zhang et al., 2005a). In situ hybridization reveals that NGL mRNAs are expressed in various regions of young and adult brains including hippocampus (Kim et al., 2006). Unlike netrin-G1 and netrin-G2, which show largely nonoverlapping distribution patterns, NGLs show largely overlapping, although distinct, mRNA distribution patterns. A possible explanation for this difference is that a single postsynaptic neuron expressing multiple NGLs may receive inputs from several axons with different origins and distinct netrin-G expression patterns. At the protein level, NGL proteins are detected mainly in brain (Kim et al., 2006).

NGLs interact with PSD-95 through their C-terminal PDZbinding motifs (Kim et al., 2006). NGLs bind to the first two PDZ domains of PSD-95 (Kim et al., 2006), unlike the situation with neuroligin, which binds to the third PDZ domain (Irie et al., 1997). Consistent with their PSD-95 interaction, NGLs are enriched in PSD fractions, detected at excitatory but not inhibitory synapses, ultrastructurally localized mainly to the postsynaptic side of spine synapses, and form a complex with PSD-95 in vivo (Kim et al., 2006). The tripartite interaction among netrin-G, NGL, and PSD-95 suggests that these proteins may couple trans-synaptic adhesion to the differentiation of the postsynaptic side of spine synapses, in a manner analogous to the activity of the tripartite complex of neurexin, neuroligin, and PSD-95 (Fig. 2). Although NGL-1 is implicated in the outgrowth and migration of neurons during embryonic brain development (Lin et al., 2003), postnatal brains display higher levels of NGL expression (Kim et al., 2006), suggesting that NGLs may have additional roles in the later stages of neuronal development. Recently, a novel role for NGL-2 in the regulation of excitatory synapse formation has been suggested (Kim et al., 2006). NGL2 expressed in nonneural cells, or coated onto beads, induces morphological and functional presynaptic differentiation in contacting axons of cocultured neurons. Direct aggregation of NGL-2 on the surface membrane of dendrites induces the clustering of postsynaptic proteins including PSD-95, GKAP, Shank, and NMDA receptors, but not AMPA receptors. Consistently, NGL-2 knockdown reduces excitatory synapse number and mEPSC frequency without affecting inhibitory synapses. The presynapse-inducing effect of NGL-2 is likely to be mediated by netrin-G2. Although presynaptic localization of endogenous netrin-G2 has not been demonstrated, exogenous netrin-G2 is selectively targeted to axons (Kim et al., 2006). In addition, NGL-2-coated beads induce netrin-G2 (exogenous) clustering in contacting axons. However, several lines of evidence indicate that netrin-G2 may not be the only presynaptic molecule mediating the effect of NGL-2. First, netrin-G2 is a GPI-anchored protein, which lacks a cytoplasmic tail and is thus unlikely to interact with cytoplasmic proteins, although GPI-anchored proteins can stimulate intracellular signaling through their localization at lipid rafts (Horejsi et al., 1999). Second, netrin-G2-expressing heterologous cells, unlike those expressing neurexins (Graf et al., 2004; Nam and Chen, 2005), do not induce postsynaptic differentiation in contacting dendrites of coculutured neurons (Kim et al., 2006). Consistently, soluble NGL-1 alone is sufficient to block the growth of thalamocortical axons, but soluble netrin-G1 does not have this effect (Lin et al., 2003). It is therefore possible that netrin-G2 may have a coreceptor for NGL-2. In addition to PSD-95, whirlin, a protein with three PDZ domains, has been identified as a cytoplasmic binding partner of NGL-1 (Delprat et al., 2005). Whirlin is expressed in cochlear hair cells and is localized in stereocilia, the stiff microvilli located at the apex of inner hair cells. Mutations in the whirlin gene (Whrn) cause shorter stereocilia, degeneration of hair cells, and deafness in mice and humans (Holme et al.,

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2002; Mburu et al., 2003). Since the cohesion of stereocilia is important for hair cell functions, NGL-1 has been suggested to mediate this cohesion by a homophilic extracellular interaction (Delprat et al., 2005). Consistent with this, NGL-1 formed a homophilic complex under physiological Ca2+ concentrations (5–250 mM) similar to that of the extracellular fluid surrounding the hair cells. Thus, NGL-1 may play a role in the differentiation and function of hair cells. However, homophilic trans-interaction between NGL-1 proteins has not been directly demonstrated. Another suggested function for NGL-2/LRRC4 in brain is tumor suppression (Wu et al., 2006; Zhang et al., 2005a). Expression of LRRC4 transcripts is reduced in glioma biopsy samples and glioma cell lines. When exogenously expressed, NGL-2/LRRC4 inhibits proliferation of glioma cell lines, probably through effects on the ERK/Akt/NF-kBp65, STAT3, and JNK2/c-Jun signaling pathways (Wu et al., 2006). The extracellular LRR domain of NGL-2/LRRC4 is important for this regulation, suggesting that the LRR domain of NGL-2/ LRRC4 transduces extracellular signals to the cytoplasmic side. Netrin-Gs have been implicated in human brain diseases. Analysis of single nucleotide polymorphisms reveals that haplotypes of netrin-G1 and netrin-G2 are associated with schizophrenia, and mRNA expression of splice variants of netrin-G1 is reduced in schizophrenic brains (Aoki-Suzuki et al., 2005). In a single Rett syndrome patient, the netrin-G1 gene (NTNG1) is truncated by a balanced chromosomal translocation (Borg et al., 2005), although whether netrin-G1 is one of the major causes of Rett syndrome requires further study (Archer et al., 2006). Generation and analysis of transgenic mice deficient in netrin-Gs and NGLs would provide further clues as to the functions of these proteins in neuronal development, synapse formation, and association with brain disorders. 3.3. SALMs SALM (for synaptic adhesion-like molecule, also known as Lrfn) is a recently identified family of PSD-95-interacting adhesion-like molecules (Ko et al., 2006; Morimura et al., 2006; Wang et al., 2006). The name ‘‘adhesion-like’’ reflects the fact that SALM does not have any known ligands, despite its possession of several adhesion domains (see below). There are five known members in the SALM family (SALM1/Lrfn2, SALM2/Lrfn1, SALM3/Lrfn4, SALM4/Lrfn3, and SALM5/ Lrfn5). Invertebrate SALM orthologs have not been identified. SALMs contain six LRRs flanked by LRRNT and LRRCT domains, an Ig domain, and a fibronectin type III (FNIII) domain, followed by a transmembrane domain and a cytoplasmic domain with a C-terminal PDZ-binding motif (Fig. 1B). This overall domain structure of SALMs is similar to that of NGLs, except that SALMs additionally have the FNIII domain. In contrast to the extracellular domains, the cytoplasmic regions of SALMs show essentially no amino acid sequence identity, except for the C-terminal PDZ-binding motifs, suggesting that various SALMs may have distinct

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functions. In addition, a PDZ-binding motif is present in SALM1, SALM2, and SALM3, but not in SALM4 or SALM5. Northern blot analysis indicates that mRNAs of SALMs are expressed mainly in brain, although weak expression of SALM3/Lrfn4 and SALM4/Lrfn3 are seen in other tissues including heart, lung, stomach, and testis (Ko et al., 2006; Morimura et al., 2006). In situ hybridization analysis indicates that SALM mRNAs are widely expressed in various brain regions including cortex and hippocampus (Ko et al., 2006; Morimura et al., 2006). As with NGLs, a single group of neurons (i.e., CA1 pyramidal neurons) seems to express multiple SALMs. Tissue distribution patterns of SALMs at the protein level remain largely unknown, except that SALM2 is expressed mainly in brain, with weak expression in testis (Ko et al., 2006). All known SALMs are modified by N-glycosylation (Ko et al., 2006; Morimura et al., 2006). Despite the fact that SALMs have typical adhesion domains in their extracellular region, their adhesion activities have not been demonstrated. SALM2 does not trans-interact with SALM2 (Ko et al., 2006). More comprehensive work on the cis- and trans-interactions of SALMs is required. SALMs interact with PSD-95 (Ko et al., 2006; Morimura et al., 2006; Wang et al., 2006). This interaction is mediated by the C-terminal PDZ-binding motifs of SALMs and the PDZ domains of PSD-95, with the strongest interaction seen with PDZ2. SALM4 and SALM5 lacking the C-terminal PDZbinding motif do not interact with PSD-95 (Ko et al., 2006; Morimura et al., 2006). In brain, SALM1 and SALM2 form complexes with PSD-95, and with other members of the PSD95 family, including PSD-93/chapsyn-110, SAP97, and SAP102 (Ko et al., 2006; Wang et al., 2006). SALM1 overexpression in early-stage cultured hippocampal neurons promotes neurite outgrowth in a manner requiring the C-terminal PDZ-binding motif (Wang et al., 2006). This effect is not observed in late-stage cultured neurons. Western blot analysis indicates that SALM1 expression reaches a plateau by the time of birth and is then maintained at that level to adult stages. SALM1 is enriched in PSD fractions, suggesting a synaptic function for SALM1. Interestingly, SALM1 directly interacts with the NR1 subunit of NMDA receptors. In contrast, AMPA receptors do not associate with SALM1. Consistently, SALM1 overexpression in cultured neurons increases the surface expression and dendritic clustering of NMDA receptors. This effect requires the C-terminal PDZ-binding motif of SALM1, similar to SALM1-enhanced neurite outgrowth. An important question is whether SALM1 regulates the synaptic trafficking and functional characteristics of NMDA receptors, or conversely, whether NMDA receptor activation regulates SALM1-mediated functions. Expression levels of SALM2, unlike those of SALM1, gradually increase during postnatal brain development (Ko et al., 2006), suggesting that SALM2 may be more important in later-stage neurons. SALM2 distributes mainly to excitatory, but not to inhibitory, synapses, and is enriched in PSD fractions. SALM2 overexpression in cultured hippocampal neurons selectively increases the number of excitatory, but not

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inhibitory, synapses, and dendritic spines, in cultured neurons. Conversely, SALM2 knockdown decreases the number of excitatory synapses and dendritic spines, and the frequency of mEPSCs. Direct clustering of SALM2 on the dendritic surface promotes the clustering of excitatory postsynaptic proteins including PSD-95, GKAP, GluR1, and NR1, but not gephyrin. The SALM2-induced clustering of both AMPA and NMDA receptors is consistent with the biochemical association of SALM2 with these receptors, and is a feature that differs from SALM1, which selectively associates with NMDA receptors. However, SALM2 expressed in nonneural cells does not induce presynaptic differentiation in contacting axons of cocultured neurons. These results suggest that SALM2 may regulate the maturation of excitatory synapses, rather than their formation. Several important questions remain to be addressed. The specific ligands of SALMs, if any, need to be identified. The differential functions of SALMs need to be addressed. In particular, the functions of SALMs without the C-terminal PDZ-binding motif require exploration. Although NGLs are mainly localized at excitatory synapses, synaptic localization patterns of SALMs (synaptic vs. extra-synaptic, excitatory vs. inhibitory, and presynaptic vs. postsynaptic) are not known, except in the case of SALM2. 3.4. LGI1 and ADAM22 LGI1 (leucine-rich, glioma inactivated 1) is a secreted glycoprotein containing LRRs and epitempin repeats (Senechal et al., 2005; Sirerol-Piquer et al., 2006) (Fig. 1B). LGI1 was first proposed as a tumor suppressor in glial cells (Chernova et al., 1998), but a recent study reports predominant expression of LGI1 in neurons rather than in glial cells, arguing against this view (Piepoli et al., 2006). Genetic analyses of human patients indicate that LGI1 is a causative gene for a rare form of epilepsy known as autosomal dominant partial epilepsy with auditory features (ADPEAF, also known as autosomal dominant form of lateral temporal lobe epilepsy or ADLTE; OMIM 600512) (Kalachikov et al., 2002; Morante-Redolat et al., 2002). LGI1 is expressed predominantly in brain, and detected in brain regions including hippocampus and piriform cortex (Chernova et al., 1998; Kalachikov et al., 2002; Morante-Redolat et al., 2002; Senechal et al., 2005). There are three additional members of the LGI family (LGI2–LGI4), which share the same domain organization and are expressed in various brain regions (Senechal et al., 2005). Recent studies have identified novel functions of LGI1 in neuronal synapses, providing clues to how LGI1 mutations cause epilepsy syndrome (Fukata et al., 2006; Schulte et al., 2006). LGI1 was identified as a component of a protein complex affinity-purified using Kv1.1-specific antibodies (Schulte et al., 2006). Kv1.1 is a presynaptic voltage-gated potassium channel subunit, which forms heteromers with Kv1.4 and Kvb1 subunits and localizes to axonal regions including medial perforant and mossy fiber pathways in hippocampus (Monaghan et al., 2001). Consistent with the biochemical results, LGI1 colocalizes with Kv1.1, Kv1.4, and Kvb1

subunits in axonal regions of hippocampus (Schulte et al., 2006). Functionally, Kv1.1 is a non-inactivating channel. Kvb1 coassembles with and inhibits Kv1.1, transforming Kv1.1 into a rapidly inactivating channel (Rettig et al., 1994). LGI1 selectively prevents this inhibitory effect of Kvb1 on Kv1.1 (Schulte et al., 2006). LGI1 has no effect on Kv1.4, which also inhibits Kv1.1. Importantly, the effect of LGI1 is eliminated by the mutations found in ADPEAF patients. Defective regulation of Kv1.1 may therefore explain the epileptic conditions of ADPEAF patients. However, this proposed function of LGI1 as a modulator of Kv1.1 and Kvb1 ‘‘inside’’ the cell needs to be reconciled with the fact that LGI1 is a secreted glycoprotein in both heterologous cells and neurons (Bermingham et al., 2006; Fukata et al., 2006; Senechal et al., 2005; Sirerol-Piquer et al., 2006). Fukata et al. revealed a novel role for LGI1 in the regulation of synaptic transmission (Fukata et al., 2006). This study used a proteomic analysis of PSD-95-associated proteins to identify LGI1 as a novel extracellular ligand for ADAM22 (Fig. 2). ADAM22 belongs to the ADAM (a disintegrin and metalloprotease) family of membrane proteins, the members of which are known to function as adhesion molecules and metalloproteases (Novak, 2004; Yang et al., 2006). The ADAM family contains more than thirty members, and about half of these, including ADAM22, have inactive metalloprotease domains. ADAM22 contains multiple domains in the extracellular region including a prodomain, a metalloprotease domain, a disintegrin domain, a cysteine-rich domain, and an EGF-like domain, which are followed by a single transmembrane domain and a cytoplasmic domain (Fig. 1B). ADAM22 has multiple splice variants, one of which contains the C-terminal PDZ-binding motif. ADAM22 mRNAs are detected mainly in brain in Northern analysis (Sagane et al., 1998; Sagane et al., 1999). In situ hybridization indicates that ADAM22 mRNAs are expressed in various brain regions and spinal cord (Fukata et al., 2006; Sagane et al., 2005). Immunostaining, or labeling by alkalinephosphatase-fused LGI1, detects ADAM22 proteins in brain regions including hippocampus and cerebellum (Fukata et al., 2006). Reflecting the functional importance of ADAM22, mice deficient in this protein show reduced body weight, hypomyelination of peripheral nerves, and ataxia, and die before postnatal day 20, probably as a result of multiple seizures (Sagane et al., 2005). LGI1 and ADAM22 form a complex with PSD-95 and stargazin (Fukata et al., 2006). Secreted LGI1 binds selectively to ADAM22, but not to stargazin, and this binding is mediated by epitempin repeats in LGI1 and the disintegrin domain in ADAM22 (Fukata et al., 2006) (Fig. 2). ADAM22 binds to the second half of PSD-95, containing the third PDZ domain (Fukata et al., 2006), whereas stargazin binds to a nonoverlapping region (the first two PDZ domains) (Schnell et al., 2002) (Fig. 2). Indeed, ADAM22 and stargazin form a ternary complex with PSD-95, rather than competing for PSD-95 binding (Fukata et al., 2006). Consistent with the presence of both stargazin and LGI1 in the same protein complex, stargazer

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mice deficient in stargazin show absence epilepsy and ataxia (Letts et al., 1998). It is interesting to note that all proteins identified in the PSD-95 complex, including stargazin, LGI1, and ADAM22, are linked to epilepsy in the sense that KO mice lacking these proteins are epileptic. Importantly, soluble LGI1 increases the AMPA/NMDA ratio of evoked responses, and the frequency and amplitude of mEPSCs in hippocampal slices, and promotes surface expression of AMPA receptors in cultured hippocampal neurons (Fukata et al., 2006). LGI1 does not affect pairedpulse facilitation, suggesting that presynaptic properties are not affected. These LGI1 effects seem to be mediated by LGI1 binding to surface ADAM22, because preincubation with soluble ADAM22 blocks the effects of LGI1. It is possible that LGI1 binding to ADAM22 stabilizes the synaptic AMPA receptor–stargazin complex, in a manner requiring PSD-95. Although the underlying mechanism is unclear, it is distinct from that of LTP because LGI1 treatment does not occlude LTP. In support of the clinical importance of the LGI1-ADAM22 interaction, a mutation in the LGI1 gene, found in ADPEAF patients, reduces LGI1 secretion and LGI1 binding to ADAM22 (Fukata et al., 2006; Senechal et al., 2005; Sirerol-Piquer et al., 2006). Abnormal synaptic transmission may therefore cause ADPEAF. Hence, possible regulation of LGI1 secretion may be worthy of attention. Another area of future work is the exploration of additional functions of LGI1 and ADAM22. For example, the function of the LRR domain of LGI1 is unclear. In addition to ADAM22, other catalytically inactive ADAMs (ADAM11 and ADAM23) are expressed in brain (Sagane et al., 1998; Sagane et al., 1999). ADAM23, the closest homolog of ADAM22, also binds LGI1 (Fukata et al., 2006), although ADAM11 binding to LGI1 has not been shown. Intriguingly, ADAM23 KO mice show ataxia and tremor, and die within 2 weeks of birth (Mitchell et al., 2001). ADAM11 KO mice show impairments in Morris water maze and rotating rod tests (Takahashi et al., 2006). Electrophysiological analysis of these KO mice, with attention to synaptic AMPA receptor functions, might help in an understanding of the biochemical mechanisms involved. Together, these results suggest that LGI and ADAM family proteins are widely involved in the regulation of neuronal development and synaptic functions. 4. Concerted actions of PSD-95 and PSD-95-interacting adhesion molecules The increasing number of PSD-95-interacting adhesion molecules suggests that PSD-95 may be a key organizer of synaptic adhesion during development and plasticity. Aspects of PSD-95 useful for its proposed function may be the abundance of the protein, its possession of multiple domains for protein–protein interactions, and its ultrastructural location close to the postsynaptic plasma membrane. These features, along with the characteristics of PSD-95 discussed below, may assist PSD-95 to coordinate synaptic adhesion.

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4.1. Synaptic localization of adhesion molecules and PSD-95 An early event in synapse formation is the contact between axonal and dendritic structures, which involves the adhesion between surface adhesion molecules. This adhesion would initiate the clustering of cytoplasmic proteins at both pre- and postsynaptic sides. PSD-95 may be one of the first molecules recruited to the sites of early synaptic adhesion (Fig. 3A). In support of this idea, overexpression of neuroligin 1, NGL-2, SALM1, and SALM2 in cultured neurons promotes PSD-95 recruitment and clustering (Chih et al., 2005; Kim et al., 2006; Ko et al., 2006; Prange et al., 2004; Wang et al., 2006). Mislocalization of neuroligin 2 and SALM2 by high-level overexpression disperses PSD-95 to extrasynaptic sites (Graf et al., 2004; Ko et al., 2006). Clustering of neuroligins induced by b-neurexin expressed in nonneural cells, or coated onto beads, triggers coclustering of PSD-95 (Graf et al., 2004; Nam and Chen, 2005). Bead-induced direct aggregation of neuroligins, NGL-2, or SALM2 on the surface of dendrites induces PSD-95 clustering (Graf et al., 2004; Kim et al., 2006; Ko et al., 2006). Together, these results support the idea that PSD-95interacting adhesion molecules promote synaptic localization of PSD-95. Synaptic localization of PSD-95 by interacting adhesion molecules seems to occur via direct molecular interactions. In support of this, C-terminal deletion mutants of neuroligin 1, NGL-2, SALM1, and SALM2 are less efficient than wild-type molecules in inducing PSD-95 clustering (Chih et al., 2004; Kim et al., 2006; Ko et al., 2006; Nam and Chen, 2005; Prange et al., 2004; Wang et al., 2006). It should be noted, however, that neuroligins bind to the third PDZ domain of PSD-95, whereas NGL-2 and SALM2 bind mainly to the first two PDZ domains (Irie et al., 1997; Kim et al., 2006; Ko et al., 2006). In addition, synaptic localization of PSD-95 requires three distinct domains including the first two PDZ domains, but not the third (Craven et al., 1999). The neuroligin 1-induced synaptic localization of PSD-95 may therefore occur through indirect mechanisms. PSD-95-interacting adhesion molecules may not be sufficient in number to recruit all synaptic PSD-95, which is one of the most abundant proteins in the PSD (Sheng and Hoogenraad, 2007). Although the presence of additional (as yet unknown) PSD-95-interacting adhesion molecules may be a possible explanation for this apparent unbalance, there may be an alternative mechanism; that is, synaptic PSD-95 clusters may grow through self-multimerization (Christopherson et al., 2003; Hsueh et al., 1997), or multivalent interaction with PSD-95interacting scaffolds such as GKAP/SAPAP (Kim et al., 1997; Romorini et al., 2004; Takeuchi et al., 1997). Once recruited to early synapses, PSD-95 may stabilize interacting adhesion molecules (Fig. 3A). In support of this possibility, SALM1 that lacks the C-terminal PDZ-binding motif shows a markedly reduced surface expression in both heterologous cells and neurons (Wang et al., 2006). PSD-95 may stabilize synaptic adhesion molecules by suppressing their internalization or lateral diffusion.

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Fig. 3. Possible concerted actions of PSD-95 and PSD-95-interacting adhesion molecules at synapses. PSD-95 and PSD-95-interacting adhesion molecules may act together to regulate the depicted synaptic events (A–H), which may occur on dendritic filopodia or shafts of young neurons (McAllister, 2007) and/or on dendritic spines of mature neurons. (A) To form or mature synapses, PSD-95-interacting molecules may promote synaptic localization of PSD-95 (upper left), or PSD-95 may conversely enhance synaptic localization of adhesion molecules (lower left). Alternatively, both proteins may form a preformed complex and be concomitantly targeted to synapses (lower right). At the synapse, PSD-95 may stabilize interacting adhesion molecules by suppressing their lateral diffusion, or internalization (upper right). (B) PSD-95 multimers may promote multimerization of interacting adhesion molecules, enhancing their ligand binding and clustering (upper; enhanced multimerization and adhesion are indicated by thicker arrows). PSD-95 may bring two different adhesion molecules into close proximity for functional coupling (lower). (C) PSD-95 may bring adhesion molecules and NMDA receptors together for functional coupling. Note that SALM1 directly interacts with the NR1 subunit of NMDA receptors (Wang et al., 2006). (D) PSD-95 may bring adhesion molecules and AMPA receptors together for functional coupling. Binding of LGI1 (not shown) to ADAM22 promotes AMPA receptor-mediated responses (Fukata et al., 2006). (E) PSD-95 may recruit adhesion molecules to excitatory synapses to

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Synaptically recruited PSD-95 may attract additional PSD95-interacting adhesion molecules to synapses (Fig. 3A). In support of this, PSD-95 overexpression increases synaptic localization of neuroligin 1 and NGL-2, in a manner requiring the PDZ-binding C-termini of these molecules (Kim et al., 2006; Prange et al., 2004). PSD-95 also translocates neuroligin 2 from inhibitory synapses to excitatory synapses (Graf et al., 2004; Levinson et al., 2005). It is unclear, however, whether these are direct effects, at least in the case of neuroligin 1. A short cytoplasmic domain (ca. 30 aa) of neuroligin 1, located proximal to the transmembrane domain, is both required and partially sufficient for synaptic neuroligin 1 localization, whereas the C-terminus of neuroligin 1 is not important (Dresbach et al., 2004). In addition, a mutant neuroligin 1 that lacks the extracellular domain induces PSD-95 clustering at extrasynaptic sites, suggesting that the extracellular domain is also important for synaptic neuroligin localization (Chih et al., 2005; Prange et al., 2004). Moreover, alternative splicing in the extracellular domain of neuroligin 1 regulates neuroligin 1 localization at excitatory or inhibitory synapses (Chih et al., 2006). PSD-95-induced synaptic localization of neuroligin 1 may therefore occur through mechanisms other than those involving direct PDZ interaction. PSD-95 and interacting adhesion molecules may be simultaneously targeted to early synapses (Fig. 3A). A recent imaging study indicates that PSD-95 forms preassembled complexes with other postsynaptic scaffolds and neuroligin 1 in dendrites, and that these complexes recruit presynaptic proteins in contacting axons (Gerrow et al., 2006). Multiple approaches of live imaging of PSD-95 and interacting adhesion molecules during early synapse formation may provide further clues as to the nature of the assembly process. Single particle labeling and tracking of neuroligin 1 using monovalent streptavidin, which minimizes the aggregation and dysfunction of neuroligin seen when multivalent streptavidin is used, could be a useful tool (Howarth et al., 2006). 4.2. Functional modulation of adhesion molecules by PSD-95 PSD-95 is likely to affect functional aspects of interacting adhesion molecules. Adhesion molecules are often activated by multimerization, which may increase ligand binding or clustering. PSD-95 may multimerize interacting adhesion molecules through its ability to self-multimerize (Hsueh and Sheng, 1999; McGee and Bredt, 1999; Shin et al., 2000) (Fig. 3B). Some PSD-95-interacting adhesion molecules may form multimers by themselves, as has been shown for neuroligin 1, which is critical for induction of presynaptic

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differentiation (Comoletti et al., 2003; Dean et al., 2003). This, however, does not rule out the possibility that PSD-95 multimerization may act in concert with neuroligin multimerization. Whether NGLs, SALMs, or ADAM22 form selfmultimers is not known. PSD-95 may bring two different adhesion molecules into close proximity for possible functional coupling (Fig. 3B). Neuroligin 1 and NGL-2, which share the ability to induce presynaptic differentiation, bind to distinct PDZ domains of PSD-95, suggesting that they may act in parallel on the same PSD-95 molecule, rather than compete for binding. Whether neuroligin 1 and NGL-2 will have simple additive effects, or exert functional synergy, remains to be determined. 4.3. Regulation of postsynaptic receptors by adhesion molecules and PSD-95 NMDA receptors appear early at new sites of axo-dendritic contacts, although time courses of recruitment vary in different studies (Friedman et al., 2000; McAllister, 2007; Washbourne et al., 2002), suggesting that there are mechanisms that couple early synaptic adhesion to NMDA receptor recruitment. PSD95-interacting adhesion molecules, which directly or indirectly associate with NMDA receptors, may play a role (Fig. 3C). In support of this possibility, overexpression of neuroligin 1 in cultured neurons promotes synaptic clustering of NMDA receptors (Chih et al., 2005). Neurexin-induced clustering of neuroligin promotes secondary clustering of NMDA receptors (Graf et al., 2004; Nam and Chen, 2005). Direct aggregation of neuroligin 1, NGL-2, and SALM2 on the surface of dendritic plasma membrane is sufficient to promote NMDA receptor clustering (Graf et al., 2004; Kim et al., 2006; Ko et al., 2006). SALM1 directly interacts with the NR1 subunit of NMDA receptors and promotes NMDA receptor clustering (Wang et al., 2006). How do PSD-95-interacting adhesion molecules promote NMDA receptor clustering? It may occur through a direct interaction, as with SALM1, although direct interaction of neuroligins, NGLs, and other SALMs (SALM2–5) with NMDA receptors has not been demonstrated. Alternatively, it may occur indirectly through, i.e. PSD-95, or SAP102, which is expressed early during development and forms a complex with NMDA receptors (Sans et al., 2000; Washbourne et al., 2002). In support of this notion, SALM1-induced NMDA receptor clustering requires the PDZ-binding C-terminus (Wang et al., 2006). In addition, Neuroligin-induced synaptic localization of NMDA receptors is partly dependent on the PDZ-binding Cterminus of neuroligin 1 (Chih et al., 2005; Nam and Chen, 2005).

promote excitatory synapse formation while suppressing inhibitory synapse formation (dotted line). PSD-95 concentrates neuroligin 1 at excitatory synapses, and translocates neuroligin 2 from inhibitory synapses to excitatory synapses, increasing the ratio of excitatory-to-inhibitory synapses (Graf et al., 2004; Levinson and ElHusseini, 2005). (F) PSD-95 may retrogradely regulate presynaptic neurotransmitter release through adhesion molecules. PSD-95 regulates presynaptic neurotransmitter release through neuroligin 1 and b-neurexin (Futai et al., 2007). (G) PSD-95, which functionally couples NMDA receptors and nNOS (Christopherson et al., 1999; Sattler et al., 1999), may juxtapose the site of postsynaptic NO generation to the site of presynaptic neurotransmitter release, a downstream target of NO, through adhesion molecules. (H) PSD-95 may regulate adhesion molecules through activity-dependent changes in its synaptic localization or content, induced by phosphorylation (a red circle), depalmitoylation (a dotted and crooked line), or proteasome-dependent degradation (a dotted PSD-95 ellipse). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of the article.)

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Would PSD-95-interacting adhesion molecules and NMDA receptors, when brought close together by PSD-95, have functional interactions? A good example is the case of EphB receptor tyrosine kinases, which directly associate with the NR1 subunit of NMDA receptors and are implicated in synaptogenesis (Dalva et al., 2007). Ephrin-B activation of EphB receptors leads to multiple consequences; it induces direct binding and clustering of NMDA receptors, tyrosine phosphorylation and potentiation of NMDA receptors, NMDA receptor-dependent gene expression, and an increase in the number of NMDA receptor-containing postsynaptic specializations (Dalva et al., 2000; Takasu et al., 2002). In another example, NCAM forms a complex with NMDA receptors (Sytnyk et al., 2006), and NCAM-associated polysialic acid negatively regulates NMDA receptors (Hammond et al., 2006). Of note, neuroligin 1-dependent enhancement of excitatory synaptic functions requires CaM kinase II activation, which lie downstream of NMDA receptors (Chubykin et al., 2007), indicative of functional interactions between neuroligin 1 and NMDA receptors. It is conceivable that PSD-95-interacting adhesion molecules, such as SALM1, which directly interacts with NMDA receptors, may regulate NMDA receptor functions, probably in a manner requiring PSD-95. Conversely, NMDA receptor activation may also regulate SALM1 functions. AMPA receptors are targeted to NMDA receptor-only silent synapses at relatively later stages of synaptic development, promoting their maturation (Bredt and Nicoll, 2003). Neuroligin 1, NGL-2, and SALM1 show selective association with NMDA, but not AMPA, receptors (Graf et al., 2004; Kim et al., 2006; Nam and Chen, 2005; Wang et al., 2006). However, once neuroligin 1, NGL-2, and SALM1 have formed ternary complexes with PSD-95 and NMDA receptors, the resulting complex may function as a molecular platform supporting activity-dependent AMPA receptor recruitment, as shown by the enhanced AMPA receptor delivery to neurexin-induced PSD-95 clusters after NMDA receptor activation (Nam and Chen, 2005). Some PSD-95-interacting adhesion molecules form complexes with AMPA receptors (Fig. 3D). Direct aggregation of SALM2 on the dendritic surface induces coclustering of AMPA receptors, in addition to NMDA receptors (Ko et al., 2006). ADAM22 forms a tight complex with AMPA receptors, but not with NMDA receptors (Fukata et al., 2006). AMPA receptors may directly interact with ADAM22, or with SALM2. Alternatively, they may be indirectly linked through stargazin and PSD-95. Further details of these associations remain to be determined. The association of PSD-95-interacting adhesion molecules with AMPA receptors is in line with the fact that other synaptic adhesion molecules, mostly coupled to cytoplasmic PDZ proteins, regulate AMPA receptor clustering/localization and function. Dasm1 (for dendrite arborization and synapse maturation 1), an immunoglobulin family adhesion molecule that associates with the Shank and S-SCAM PDZ proteins, regulates synaptic maturation mainly by promoting synaptic AMPA receptor functions (Shi et al., 2004). SynCAM,

another immunoglobulin family adhesion molecule that binds to PDZ proteins including CASK/LIN-2, induces presynaptic differentiation in contacting axons in neuron-nonneural cell coculture assays, and reconstitutes functional synapses when coexpressed with AMPA receptors (Biederer et al., 2002). EphB2, which binds to PDZ proteins including GRIP, colocalizes with and enhances surface expression of AMPA receptors in a manner requiring its PDZ-binding C-terminus (Kayser et al., 2006). N-cadherin directly interacts with the extracellular domain of the GluR2 AMPA receptor subunit and induces AMPA receptor recruitment (Saglietti et al., 2007), consistent with the biochemical association between these proteins (Dunah et al., 2005; Nuriya and Huganir, 2006). Axonally derived neuronal pentraxins, namely Narp and NP1 (secreted proteins) and NPR (a transmembrane protein), trans-synaptically regulate the clustering and synaptic recruitment of AMPA receptors (O’Brien et al., 2002; Sia et al., 2007; Xu et al., 2003). Lastly, a recent study has shown that stargazin/TARP can mediate cell–cell adhesion when expressed in heterologous cells, suggesting that it may act as an adhesion molecule (Price et al., 2005), although further studies are required to clarify the role of stargazin in this process. 4.4. Regulation of the excitatory–inhibitory balance Recent studies on neuroligins have suggested a novel mechanism underlying the regulation of the excitatory versus inhibitory (E/I) balance in neurons. PSD-95 translocates neuroligin 2 from inhibitory to excitatory synapses, in addition to concentrating neuroligin 1 at excitatory synapses, which leads to increases in the number and function of excitatory synapses (Graf et al., 2004; Levinson et al., 2005; Levinson and El-Husseini, 2005; Prange et al., 2004). Conversely, PSD-95 knockdown reduces the ratio of excitatory-to-inhibitory synapses (Prange et al., 2004). These results suggest that PSD-95-dependent localization of neuroligins at specific synapses regulates the E/I balance of a neuron (Fig. 3E). By analogy with neuroligins, other PSD-95-interacting adhesion molecules may also participate in the regulation of the E/I balance (Fig. 3E). PSD-95 promotes excitatory synaptic localization of NGL-2 (Kim et al., 2006) and perhaps other adhesion molecules, which would act in concert with neuroligins to regulate the formation and function of excitatory synapses. Conversely, dispersal or degradation of synaptic PSD-95 would suppress synaptic concentration of PSD-95interacting adhesion molecules and lead to the loss of excitatory synapses. It is not known whether any members of the NGL and SALM families are localized at inhibitory synapses. 4.5. Presynaptic induction and retrograde modulation Pre- and postsynaptic sides of neuronal synapses exhibit a high degree of structural and functional correlations, probably through bidirectional communication (Bourne and Harris, 2007). Molecules mediating this correlation include synaptic adhesion molecules, and anterogradely or retrogradely secreted

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molecules such as neurotransmitters, endocannabinoids, neurotrophins, and nitric oxide (NO) (Tao and Poo, 2001). Because PSD-95 is linked through neuroligins to presynaptic neurexins, this tripartite complex may function as a key axis through which postsynaptic PSD-95 regulates presynaptic differentiation and functions (Fig. 3F). In support of this, PSD95 overexpression promotes synaptic clustering of neuroligin as well as synapsin (a presynaptic marker) (Prange et al., 2004). A preformed complex of PSD-95, GKAP, and Shank can recruit presynaptic molecules (Gerrow et al., 2006). Functionally, PSD-95 and neuroligin 1 increase the presynaptic release probability, and the effect of PSD-95 is decreased by suppressing the expression, or function, of neuroligin 1 (Futai et al., 2007). In addition, a dominant negative b-neurexin mutant reduces the release probability, suggesting that bneurexin is a presynaptic mediator (Futai et al., 2007). SAP97, a PSD-95 relative, similarly enhances presynaptic structure and function when it is overexpressed in cultured neurons (Regalado et al., 2006). Interestingly, the effect is independent of neuroligin and neurexin. Instead, it requires other adhesion molecules including cadherins, integrins, and EphB/ephrin-B (Regalado et al., 2006), suggesting that diverse molecular mechanisms regulate trans-synaptic modulation. Given these results, PSD-95-interacting adhesion molecules may also mediate PSD-95-dependent-regulation of presynaptic functions (Fig. 3F). Postsynaptically released NO activates presynaptic guanylyl cyclase for cGMP production, which ultimately accelerates synaptic vesicle cycling for sustained neurotransmitter release (Micheva et al., 2003). PSD-95 forms a ternary complex with NMDA receptors and nNOS to facilitate their functional coupling (Christopherson et al., 1999; Sattler et al., 1999). By analogy, PSD-95 may bring nNOS close to neuroliginassociated presynaptic release sites for NO-dependent transsynaptic regulation of presynaptic activities (Fig. 3G).

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including adhesion molecules. In addition, changes in the functional strength of synapses are coupled to structural changes in synapses. For example, plasticity-inducing stimuli affect spine formation and growth, and induce changes in PSD size, F-actin polymerization, membrane and protein traffic, and trans-synaptic adhesion (Bredt and Nicoll, 2003; Dalva et al., 2007; Kennedy and Ehlers, 2006; Tada and Sheng, 2006). Indeed, LTP/LTD modulation by adhesion molecules including NCAM, N-cadherin, and Eph receptor-ephrin has been reported (Contractor et al., 2002; Luthl et al., 1994; Tang et al., 1998). Generation of relevant KO mice may help address the question. 5. Conclusions In this review, we have discussed both basic aspects, and the functional importance, of PSD-95 and PSD-95-interacting adhesion molecules in steps of synapse development, including synapse formation, maturation, and possibly plasticity. PSD-95 and PSD-95-interacting molecules may act in concert to regulate their synaptic localization and clustering. They may act together to regulate the synaptic localization of NMDA and AMPA receptors, and to coordinate trans-synaptic communications occurring through direct protein interactions or diffusible molecules. They may constitute a molecular platform whereby functional plasticity in the synapse is coupled to structural plasticity. Lastly, PSD-95-interacting adhesion molecules may be key mediators of PSD-95 functions, which include the regulation of synaptic structure, strength, and plasticity. Acknowledgment This work was supported by the Creative Research Initiative Program of the Korean Ministry of Science and Technology (to E.K.).

4.6. Activity-dependent regulation of synaptic adhesion Neuronal activity regulates adhesion molecules. For instance, NMDA receptor activation promotes dimerization and protease resistance of N-cadherin (Tanaka et al., 2000). LTP-inducing stimuli promote synaptic localization of NCAM180 (Schuster et al., 1998). Expression, synaptic localization, and degradation of PSD-95 are regulated by neuronal activities and various mediators including glutamate receptors (NMDA and metabotropic), neuregulin-1, FMRP, Akt, SNK, SPAR, and protein modifying enzymes (palmitoylation and phosphorylation). PSD-95 has significant impacts on the synaptic localization and functions of PSD-95-interacting adhesion molecules. Changes in the synaptic localization of PSD-95, i.e., activity-dependent dispersal or degradation, are thus likely to subsequently regulate interacting adhesion molecules (Fig. 3H). It is not known whether LTP or LTD is regulated by PSD-95interacting adhesion molecules. PSD-95, however, is implicated in the regulation of both LTP and LTD, and such regulation may depend on diverse PSD-95-interacting proteins

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