Cell adhesion molecules (CAMs) mediate many critical processes in the mammalian brain, including formation and maturation of synapses. CAMs have been implicated in cognitive diseases, such as autism and schizophrenia, as candidate genes. These studies highlight the importance of understanding the mechanisms by which CAMs participate in normal and pathophysiological conditions. Synaptic adhesion-like molecules (SALMs) are a new family of CAMs that are expressed in the mammalian brain. The five SALM family members (SALM1-5) have conserved extracellular N-termini, but differ substantially in their intracellular C-termini. The distinct C-termini suggest the SALMs possess unique functions. In recent studies, over-expression of SALM2 increased the number of excitatory synapses and reduction of SALM5 expression decreased the number of inhibitory synapses. Furthermore, SALM1 directly interacted with the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor. NMDA receptors are key mediators of glutamatergic transmission in mammalian brains and thus a SALM/NMDA receptor interaction would have important functional consequences for excitatory synapses. The mechanisms underlying roles that SALMs play at the synapses and in the functioning of NMDA receptors remain unknown. In this proposal, we will identify regions within SALMs that regulate the formation and maturation of synapses. We will also identify regions critical for the SALM/NMDA receptor interaction, the cellular compartments where the interaction occurs and the role that SALMs play in NMDA receptor functioning. These studies will be carried out using immunocytochemistry, biochemistry and electrophysiology on heterologous cells, dissociated cultures of cerebellar granule cells and hippocampal neurons. Determination of the mechanisms by which SALMs regulate synapses and NMDA receptors is crucial for our understanding of synapse functioning as well as for discerning the etiology of diseases associated with CAMs.