Abstract
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 (SALM1) as a constituent of the proposed presynaptic Munc18/CASK/Mint1/Lin7b organizer complex. SALM1 preferentially localized to presynaptic compartments of excitatory hippocampal neurons. SALM1 depletion in excitatory hippocampal primary neurons impaired Neurexin1β‐ and Neuroligin1‐mediated excitatory synaptogenesis and reduced synaptic vesicle clustering, synaptic transmission, and synaptic vesicle release. SALM1 promoted Neurexin1β clustering in an F‐actin‐ and PIP2‐dependent manner. Two basic residues in SALM1's juxtamembrane polybasic domain are essential for this clustering. Together, these data show that SALM1 is a presynaptic organizer of synapse development by promoting F‐actin/PIP2‐dependent clustering of Neurexin.
Highlights
Establishing brain connectivity involves the precise targeting of billions of axons to their specific targets followed by the development of functional synapses
We show that synaptic adhesion-like molecule 1 (SALM1) is present at pre- and postsynaptic membranes of mouse hippocampal neurons and that depletion of pre- or postsynaptic SALM1 impaired Neuroligin1- and Neurexin1b-mediated excitatory synapse formation and reduced synaptic vesicle clustering, synaptic transmission, and synaptic vesicle release
The cell adhesion molecule SALM1, previously described as a postsynaptic protein (Lie et al, 2018), was the only adhesion molecule identified as a putative interactor of the CASK/Mint1/Lin7b presynaptic complex (Fig 1A and Appendix Fig S1A)
Summary
Establishing brain connectivity involves the precise targeting of billions of axons to their specific targets followed by the development of functional synapses. The selective expression of different CAMs is considered a major determinant of synaptic diversity (Fuccillo et al, 2015; Foldy et al, 2016; de Wit & Ghosh, 2016). How these individual components work together to establish brain connectivity is still largely unknown. Cis- and trans-interactions can be competitive or cooperative resulting in a complex interplay between different CAMs and their downstream effectors in individual synapses (Aricescu & Jones, 2007; Taniguchi et al, 2007; Lie et al, 2016). How different CAMs are organized in individual synapses and how they organize pre- and postsynaptic specializations is still poorly understood
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