Cell adhesion molecules: signalling functions at the synapse

Key Points Cell adhesion molecules are present at synaptic sites throughout the lifetime of a synapse and are involved in the formation, function and plasticity of synaptic connections. Synaptically localized cell adhesion molecules (SAMs), are multifunctional molecules that coordinate different aspects of synaptic development and function through specialized signalling or protein–protein interaction motifs. Neurexin–neuroligin signalling has a role in the development of pre- and postsynaptic terminals at both excitatory and inhibitory synapses. Recent in vivo data indicates that these molecules are most important for the proper maturation and function of synaptic contacts. The EphB receptor tyrosine kinase regulates excitatory synaptogenesis, including the clustering of NMDARs ( N -methyl- D -aspartate receptors) and AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors), dendritic spine formation and presynaptic differentiation. EphB-mediated signalling seems to be particularly significant for a subset of synaptic inputs in vivo . A number of molecules belonging to the immunoglobulin superfamily of proteins (synaptic cell adhesion molecule (SynCAM), synaptic adhesion-like molecule (SALM) and netrin G2 ligand (NGL2)) also contain intracellular PDZ binding domains that permit interactions with the postsynaptic scaffold protein PSD-95 (postsynaptic density protein-95). Each of these trans-synaptic signals can control aspects of excitatory synapse formation in vitro . Cadherins signal via catenins to regulate dendritic spine morphology and motility. In addition, in vivo work has shown that the loss of particular catenin molecules results in abnormal synapse formation and/or maturation. Ephs and ephrins regulate two mechanistically distinct forms of long-term potentiation in the hippocampus. At the mossy fibre–CA3 synapse this occurs downstream of a transynaptic interaction between postsynaptic EphB and presynaptic ephrin-B, whereas at the Schaeffer collateral–CA1 synapse the mechanism is less clear. Multiple lines of evidence indicate that neural cell adhesion molecule and cadherin regulate hippocampal synaptic plasticity. Both molecules possess multiple adhesive and signalling functions that could be important for plasticity, but the exact mechanisms by which these molecules regulate these functions are not clear. Cell adhesion molecules localized at synapses do more than provide a physical link between pre and post-synaptic cells. Dalva a