[SY7.3]: SynCAM complexes encode synaptic adhesion to organize nascent synapses

Synapses allow neurons to communicate with each other, and the function as well as the asymmetric structure of mature synapses is well described. In contrast, the molecular signals that differentiate nascent synapses remain poorly understood. A select group of synaptic adhesion molecules is now known to function in synapse development.We here define SynCAMproteins as a family of four synaptic cell adhesion molecules that organize synapses. SynCAMs are specific for vertebrates and comprise of four membrane proteins belonging to the immunoglobulin super family. To place SynCAMs within the context of brain development, we analyzed their expression patterns and found that all SynCAMs are predominantlyexpressed inneuronsthroughout thedevelopingand adult central nervous system. They are expressed in the majority of neurons, indicating that they are of general relevance for neuronal differentiation, and can be differentially expressed within brain regions. Within neurons, SynCAMs are present in synaptic plasma membranes and localize to excitatory and to a lesser extent also to inhibitory synapses. To understand their extracellular interactions, we analyzed their adhesive binding and found that SynCAMsengage each other in specific heterophilic adhesive interactions that complement their differential expression patterns in brain. These heterophilic interactions are preferred over the homophilic binding that SynCAMs 1, 2 and 3 can exert. The SynCAM 1/2 adhesion complex is representative of heterophilic SynCAM interactions in synaptic membranes. SynCAM 1 and 2 engage each other into a highly specific and stable trans-synaptic adhesion complex. The assemblyofthistrans-synapticSynCAM1/2complexisaccompanied by synapticmembrane differentiation in cultured neurons. Notably, SynCAM 1 and 2 promote synaptogenesis and synaptic function as they increase the number of active presynaptic terminals and enhance excitatory neurotransmission. These trans interactions of SynCAMs are affected by glycosylation, indicating regulation of this novelsynapticadhesioncomplexbypost-translationalmodification. Together, we define SynCAM proteins as components of novel heterophilic trans-synaptic adhesion complexes. Our results elucidate the composition of trans-synaptic adhesion complexes and provide insight into the mechanisms guiding synaptic membrane organization across the synaptic cleft.