Synaptic cell adhesion

Abstract

Chemical synapses are asymmetric intercellular junctions that mediate synaptic transmission. Synaptic junctions are organized by trans-synaptic cell adhesion molecules bridging the synaptic cleft. Synaptic cell adhesion molecules not only connect pre- and postsynaptic 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 organizing 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.

Figure 1.

Synaptic cell adhesion and synaptic function. Synaptic cell adhesion involves multiple, partially overlapping 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 properties 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.

Figure 2.

The case of neurexins/neuroligins. Presynaptic neurexins (red) and postsynaptic neuroligin dimers (green) associate in a Ca²⁺-dependent manner to form a prototypical trans-synaptic complex that reflects the asymmetric architecture of chemical synapses. The sixth LNS domain of α-neurexins and the corresponding single LNS domain of β-neurexins both bind to neuroligins via hydrophobic interactions that bury the Ca²⁺-ion in the interface. Genetic deletion studies in mice revealed the essential role of both gene families at synapses because triple knockouts of either neurexin-1α/2α/3α or of neuroligin-1/2/3 are perinatally lethal, and show dramatic impairments in synaptic function as summarized in the text box (arrows indicate direction of change). Note that α-neurexins and neuroligins are not essential for the formation of synaptic contacts in the brain. The space filling models of the extracellular sequences of neurexins and neuroligins are based on homology modeling of available crystal data, and are presented approximately to scale in the synaptic cleft. (Full-length structures of synaptic cell adhesion proteins and of postsynaptic receptors as shown in Figures 2–4 were modeled using coordinates from the protein data bank (http://www.pdb.org), models from ModBase (http://modbase.compbio.ucsf.edu), SWISS-MODEL Repository (http://swissmodel.expasy.org/repository/) and Phyre (http://www.sbg.bio.ic.ac.uk/~phyre/). Missing structures were modeled manually using BLAST2MODEL (http://dunbrack.fccc.edu) and program SPDPV (http://spdbv.vital-it.ch/). The complex structures were visualized using the open source program pymol (http://sourceforge.net/projects/pymol/).

Figure 3.

Neurexins as synaptic anchors for macromolecular complexes. Because of the versatile nature of their LNS domains, α- and β-neurexins can interact with several binding partners (see insets) that either compete for the same interaction site such as neuroligin-1 and LRRTM2, or may bind at completely different sites such as neurexophilin. Because neuroligins form dimers, mixed complexes of α- and β-neurexins with neuroligin may exist, and may even recruit additional binding partners of α-neurexins, possibly leading to large multimolecular clusters. Direct or indirect association with ligand- or voltage-dependent ion channels (e.g., GABA_AR, GluR, NMDAR, Ca_V2.x, see text for discussion) provides a means of determining synaptic properties or modulating synaptic strength. The space filling models of neurexins and their binding partners are based on homology modeling of available crystal data, and are presented approximately to scale in the synaptic cleft.

Figure 4.

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