Splicing-Dependent Trans-synaptic SALM3–LAR-RPTP Interactions Regulate Excitatory Synapse Development and Locomotion

Abstract

SUMMARY Synaptic adhesion molecules regulate diverse aspects of synapse development and plasticity. SALM3 is a PSD-95-interacting synaptic adhesion molecule known to induce presynaptic differentiation in contacting axons, but little is known about its presynaptic receptors and in vivo functions. Here, we identify an interaction between SALM3 and LAR family receptor protein tyrosine phosphatases (LAR-RPTPs) that requires the mini-exon B splice insert in LAR-RPTPs. In addition, SALM3-dependent presynaptic differentiation requires all three types of LAR-RPTPs. SALM3 mutant (Salm3−/−) mice display markedly reduced excitatory synapse number but normal synaptic plasticity in the hippocampal CA1 region. Salm3−/− mice exhibit hypoactivity in both novel and familiar environments but perform normally in learning and memory tests administered. These results suggest that SALM3 regulates excitatory synapse development and locomotion behavior.

An alternative splicing switch shapes neurexin repertoires in principal neurons versus interneurons in the mouse hippocampus

“…For example, synaptic partners express matching pairs of adhesive factors or afferents are repelled from inappropriate targets through chemorepulsive signaling molecules (Sanes and Yamagata, 2009; Shen and Scheiffele, 2010). Gene families encoding large numbers of isoforms generated through multiple genes, alternative promoters and extensive alternative splicing, hold the potential to generate recognition tags for specific trans-synaptic interactions (Baudouin and Scheiffele, 2010; Reissner et al, 2013; Takahashi and Craig, 2013; Schreiner et al, 2014b; Li et al, 2015). However, given the difficulty of mapping endogenous splice isoform repertoires it is poorly understood how splice isoforms are differentially distributed across neuronal cell types.…”

Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice

“…The role of Lrfn2/SALM1 in synapse maturation is well contrasted with excitatory synapse number regulation by Lrfn4/SALM3 and Lrfn3/SALM4. Lrfn4/SALM3 KO mice show normal hippocampal CA1 synaptic morphology and plasticity, and normal memory functions whereas the excitatory synapse density is decreased62. SALM4 negatively regulates excitatory synapses via cis inhibition of SALM3 (ref.…”

Transcellular Nanoalignment of Synaptic Function

“…A further candidate molecular linkage from active zone to cleft is provided by Liprin-α, which binds to RIM (Schoch et al, 2002) as well as transmembrane protein tyrosine phosphatases of the LAR family (Serra-Pages et al, 1998). LAR proteins interact with a variety of postsynaptic membrane proteins that control excitatory synapse development including NGL/LRRC (Netrin-G ligand/Leucine-rich repeat-containing protein), Slitrks (Slit- and Trk-like proteins), and SALM proteins (synaptic adhesion-like molecules) (Beaubien et al, 2016; Choi et al, 2016; Li et al, 2015; Woo et al, 2009; Yim et al, 2013) and thus may bridge the cleft. Nevertheless, the existence of a LAR-Liprin-RIM complex at the active zone remains tentative, and the subcellular distribution of the Liprin and LAR proteins and postsynaptic LAR partners are incompletely documented.…”