Arias-Aragon_2025_Mol.Brain_18_20

Neurexins are presynaptic plasma membrane proteins that regulate key aspects of synapse physiology through the formation of transcellular complexes with postsynaptic ligands, including neuroligins (Nlgns). Each neurexin gene (NRXN1-3) generates two main alternative-spliced transcripts that generate alpha and beta-Nrxn isoforms differing in their extracellular domains. Mutations in NRXN1 are associated with autism and other neurodevelopmental disorders. However, whether dysfunction of NRXN1 occurs through common or isoform-specific postsynaptic partners for alpha- and beta-Nrxn1 is not completely known. The association of Nrxn1 proteins with postsynaptic partners has been mostly analysed in experiments that test binding, but Nrxn proteins must interact with Nlgns in opposing cells, which requires transcellular oligomerization. Here, we studied the interactions of Nrxn1/Nlgn pairs across the synapse and identified the type of association affected in a mouse model of autism. We found that beta-Nrxn1 can be recruited at synaptic contacts by glutamatergic Nlgn1 and GABAergic Nlgn2, whereas alpha-Nrxn1 is a presynaptic partner of Nlgn2. Insertion of alternative spliced segment 4 (AS4) negatively modulates the presynaptic recruitment of Nrxn1 by Nlgns. These data obtained in transcellular assays help clarify previous knowledge based on the ability of Nrxn1 to bind to Nlgns. Interestingly, we found that a mutant beta-Nrxn1 shows ligand restriction for glutamatergic Nlgn1 in the brain of a mouse model of autism. These findings suggest that autism-associated mutations affecting beta-Nrxn1 can act through specific synaptic partners that may be different from those of its alpha-Nrxn1 counterparts.