Abstract
Synaptic adhesion molecules regulate various aspects of synapse development, function and plasticity. These functions mainly involve trans-synaptic interactions and positive regulations, whereas cis-interactions and negative regulation are less understood. Here we report that SALM4, a member of the SALM/Lrfn family of synaptic adhesion molecules, suppresses excitatory synapse development through cis inhibition of SALM3, another SALM family protein with synaptogenic activity. Salm4-mutant (Salm4−/−) mice show increased excitatory synapse numbers in the hippocampus. SALM4 cis-interacts with SALM3, inhibits trans-synaptic SALM3 interaction with presynaptic LAR family receptor tyrosine phosphatases and suppresses SALM3-dependent presynaptic differentiation. Importantly, deletion of Salm3 in Salm4−/− mice (Salm3−/−; Salm4−/−) normalizes the increased excitatory synapse number. These results suggest that SALM4 negatively regulates excitatory synapses via cis inhibition of the trans-synaptic SALM3–LAR adhesion.
Highlights
Synaptic adhesion molecules regulate various aspects of synapse development, function and plasticity
SALM4 proteins were detected in synaptic brain fractions, including crude synaptosomes, synaptic membranes and postsynaptic density (PSD) fractions (Fig. 1e,f and Supplementary Fig. 1e,f), consistent with the previously reported ultrastructural localization of SALM4 proteins around cell junctions, including neuronal synapses[20]
Our data indicate that a SALM4 mutant that lacks SALM3 binding (SALM4-Ecto), unlike full-length SALM4, loses the ability to inhibit LAR binding to SALM3 in HEK293T cells, and to rescue the increased miniature excitatory postsynaptic currents (mEPSCs) frequency in CA1 pyramidal cells (Fig. 7d–f)
Summary
Synaptic adhesion molecules regulate various aspects of synapse development, function and plasticity These functions mainly involve trans-synaptic interactions and positive regulations, whereas cis-interactions and negative regulation are less understood. Deletion of Salm[3] in Salm[4] À / À mice (Salm[3] À / À ; Salm[4] À / À ) normalizes the increased excitatory synapse number These results suggest that SALM4 negatively regulates excitatory synapses via cis inhibition of the trans-synaptic SALM3–LAR adhesion. In addition to these cis-interactions, SALMs can participate in trans-interactions, with SALM4 and -5 forming homophilic and trans-cellular adhesion complexes[20] These results suggest that the individual SALM isoforms are unlikely to be physically or functionally isolated, but instead may participate in intricate interplays with other SALM isoforms.
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