SALM 1 controls synapse development by promoting F‐actin/PIP2‐dependent Neurexin clustering

Synapse development requires spatiotemporally regulated recruitment of synaptic proteins. In this study, we describe a novel presynaptic mechanism of cis ‐regulated oligomerization of adhesion molecules that controls synaptogenesis. We identified synaptic adhesion‐like molecule 1 ( SALM 1) as a constituent of the proposed presynaptic Munc18/ CASK /Mint1/Lin7b organizer complex. SALM 1 preferentially localized to presynaptic compartments of excitatory hippocampal neurons. SALM 1 depletion in excitatory hippocampal primary neurons impaired Neurexin1β‐ and Neuroligin1‐mediated excitatory synaptogenesis and reduced synaptic vesicle clustering, synaptic transmission, and synaptic vesicle release. SALM 1 promoted Neurexin1β clustering in an F‐actin‐ and PIP 2‐dependent manner. Two basic residues in SALM 1's juxtamembrane polybasic domain are essential for this clustering. Together, these data show that SALM 1 is a presynaptic organizer of synapse development by promoting F‐actin/ PIP 2‐dependent clustering of Neurexin.