Abstract
Post-transcriptional mechanisms regulating cell surface synaptic organizing complexes that control the properties of connections in brain circuits are poorly understood. Alternative splicing regulates the prototypical synaptic organizing complex, neuroligin-neurexin. In contrast to the well-studied neuroligin splice site B, little is known about splice site A. We discovered that inclusion of the positively charged A1 insert in mouse neuroligin-1 increases its binding to heparan sulphate, a modification on neurexin. The A1 insert increases neurexin recruitment, presynaptic differentiation, and synaptic transmission mediated by neuroligin-1. We propose that the A1 insert could be a target for alleviating the consequences of deleterious NLGN1/3 mutations, supported by assays with the autism-linked neuroligin-1-P89L mutant. An enrichment of neuroligin-1 A1 in GABAergic neuron types suggests a role in synchrony of cortical circuits. Altogether, these data reveal an unusual mode by which neuroligin splicing controls synapse development through protein-glycan interaction and identify it as a potential therapeutic target.
Highlights
Synapses are specialized sites of intercellular communication where chemical transmission occurs between neurons in brain circuits
We wondered whether the A1 insert with its high density of positively charged surface residues might participate in binding of NLGN to the heparan sulphate (HS) chain of NRXN
In contrast to the well-studied NLGN1 B splice site, the A splice site has been poorly studied, with information previously lacking on the A1 insert
Summary
Synapses are specialized sites of intercellular communication where chemical transmission occurs between neurons in brain circuits. NLGNs have additional extracellular domain binding partners, cell surface MDGAs, linked to neuropsychiatric disorders (Connor et al, 2019). The major form of NLGN1 contains this B insert but lacks an insert at splice site A (Chih et al, 2006). The NLGN A inserts have little effect on interaction with NRXN or MDGA protein domains (Comoletti et al, 2006; Elegheert et al, 2017; Koehnke et al, 2010). We further report cell type regulation of A1 insertion, identify Rbfox as potential regulators, and show that A1 insertion can partially restore function of an ASD-linked missense variant of NLGN1
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