Abstract
Synaptogenic adhesion molecules play critical roles in synapse formation. SALM5/Lrfn5, a SALM/Lrfn family adhesion molecule implicated in autism spectrum disorders (ASDs) and schizophrenia, induces presynaptic differentiation in contacting axons, but its presynaptic ligand remains unknown. We found that SALM5 interacts with the Ig domains of LAR family receptor protein tyrosine phosphatases (LAR-RPTPs; LAR, PTPδ, and PTPσ). These interactions are strongly inhibited by the splice insert B in the Ig domain region of LAR-RPTPs, and mediate SALM5-dependent presynaptic differentiation in contacting axons. In addition, SALM5 regulates AMPA receptor-mediated synaptic transmission through mechanisms involving the interaction of postsynaptic SALM5 with presynaptic LAR-RPTPs. These results suggest that postsynaptic SALM5 promotes synapse development by trans-synaptically interacting with presynaptic LAR-RPTPs and is important for the regulation of excitatory synaptic strength.
Highlights
SALM5/Lrfn[5] has been associated with severe progressive autism in which expression levels of SALM5 are markedly reduced due to a balanced chromosomal translocation[19,20,21,22,23]
In order to identify a presynaptic ligand for SALM5, we performed cell aggregation assays in which one group of L cells expressing SALM5 was mixed with another group of L cells expressing candidate adhesion molecules (Supplementary Fig. 1)
We found that SALM5-expressing cells coaggregated with cells expressing all three LAR-RPTPs (LAR, PTPδ, and PTPσ)
Summary
SALM5/Lrfn[5] has been associated with severe progressive autism in which expression levels of SALM5 are markedly reduced (by ~90%) due to a balanced chromosomal translocation[19,20,21,22,23]. LAR-RPTPs interact trans-synaptically with several postsynaptic adhesion molecules, including NGL-3, TrkC, IL1RAPL1, IL1RAcP, Slitrks, and SALM3 to promote synapse development[30,31,32,33,34,35,36,37,38,39], and in cis manner with presynaptic glypicans and netrin-G140,41. Supporting their significant in vivo functions, mice lacking LAR, PTPδ, or PTPσexhibit a variety of phenotypes, including reduced food intake and survival, endocrine defects, reduced neuronal growth and regeneration, altered synaptic plasticity, impaired learning and memory, and hyperactivity[42,43,44,45,46,47,48,49,50]. We found that SALM5 maintains AMPA receptor (AMPAR)-mediated excitatory synaptic transmission through mechanisms involving the interaction of SALM5 with LAR-RPTPs
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