The resilient synapse: insights from genetic interference of synaptic cell adhesion molecules

Synaptic cell adhesion molecules (SCAMs) are mostly membrane-anchored molecules with extracellular domains that extend into the synaptic cleft. Prototypical SCAMs interact with homologous or heterologous molecules on the surface of adjacent cells, ensuring the precise apposition of pre- and postsynaptic elements. More recent definitions of SCAMs often include molecules involved in axon pathfinding, cell recognition and synaptic differentiation events, making SCAMs functionally and molecularly a highly diverse group. In this review, we summarize the proposed in vivo functions of a large variety of SCAMs. We mainly focus on results obtained from analyses of genetic model organisms, mostly mouse knockout mutants, lacking expression of the respective candidate genes. In contrast to the substantial effect yielded by some knockouts of molecules involved in synaptic vesicle release, no SCAM mutant has been reported thus far that shows a prominently altered structure of the majority of synapses or even lacks synapses altogether. This surprising resilience of synaptic structure might be explained by a high redundancy between different SCAMs, by the assumption that the crucial molecular players in synapse structure have yet to be discovered or by a grand variability in the mechanisms of synapse formation that underlies the diversity of synapses. Whatever the final answer turns out to be, the genetic dissection of the SCAM superfamilies has led to a much better understanding of the different steps required to form, differentiate and modify a synapse.