Sexually dimorphic control of excitatory synapse maintenance in ventral hippocampal circuits by Neurexin2α ligand Vstm2b

Abstract Neuronal networks rely on precise synapse formation, maturation, and maintenance orchestrated by synaptic adhesion molecules including α- and β-neurexins (Nrxns). Through unbiased proteomics, we identified Vstm2 family members as α-Nrxn-specific interactors that require inclusion of an insert at alternative splice site 2 (SS2) in α-Nrxns. In particular, as a selective ligand of axonal Nrxn2α SS2+ , Vstm2b promotes glutamatergic presynaptic assembly. Loss of Vstm2b in mice impairs glutamatergic synaptic function and maintenance in the ventral hippocampal CA1 (vCA1), while leaving early synaptogenesis intact. These impairments are sex- and input-specific, highlighting distinct circuit vulnerabilities in male and female mice. Accordingly, Vstm2b knockout mice exhibit sexually dimorphic anxiety-related behaviors and social deficits. Our findings establish the Vstm2b-Nrxn2α synaptic adhesion complex as a critical regulator of vCA1 excitatory synapse stability and functional organization and reveal the α-Nrxn-centered interactome as a key driver of sex-dependent synaptic specificity and circuit functions that underlie social behavior and anxiety.