SynCAMs extend their functions beyond the synapse.

Synaptic cell adhesion molecules are characterized by their potential to trigger synaptogenesis in vitro, even when expressed in non-neuronal cell lines. In addition to the prototypic synaptic cell adhesion molecules (SynCAMs), other structurally unrelated families of synaptic cell adhesion molecules have been identified: neurexins and neuroligins, as well as the leucine-rich repeat transmembrane neuronal protein family. Although in vivo the absence of individual synaptic cell adhesion molecules does not necessarily reduce the number of synapses, it does affect the function of synapses. Not surprisingly, mutations in synaptic cell adhesion molecules have been identified in patients suffering from neurodevelopmental disorders, such as autism spectrum disorders, intellectual disability or schizophrenia. In line with the major function of these genes at the synapse, their role in the pathogenesis of neurodevelopmental diseases has been attributed to synaptogenesis, synapse maintenance and synaptic plasticity. However, one family of synaptic cell adhesion molecules, the SynCAMs, have also been implicated in axon guidance, that is, an earlier step in neural circuit formation. These findings suggest that SynCAMs, and maybe other families of synaptic cell adhesion molecules as well, could contribute to the pathogenesis of neurodevelopmental disorders at multiple steps of neural circuit formation and, thus, shape the distinct symptoms associated with different disease variants or distinct neurodevelopmental disorders in addition to their effect on synaptic function. In this review, we summarize the roles of one family of synaptic cell adhesion molecules, the SynCAMs, at the synapse and beyond in axon guidance and myelination.