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Synaptic Cell Adhesion Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press 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 synapses 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 neurexins and neuroligins, 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 brain 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). synapse 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 1 Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press M. Missler et al. to define its span (Palade and Palay 1954; Gray ture synapses. The molecular assembly stage 1959). During synaptogenesis, 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 memory 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 cell adhesion molecule 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 synaptic plasticity (Fig. 1). b-sandwich fold. Contact establishment involves recognition of Cadherin domains. Cadherin domains are pre- and postsynaptic neurons at the site of fu- characterized by an all-b fold, and always occur 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a005694 Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press 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, neurexin, 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
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