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

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 Nrxn2αSS2+, 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. The authors thank Denis Faubert, Josée Champagne, Marguerite Boulos, and Sylvain Tessier from the IRCM Mass Spectrometry and Proteomics Platform for their technical expertise and support. The authors also acknowledge support from the Sealy Center for Structural Biology at UTMB, Sonia Bélanger from the IRCM Animal Facilities for animal care and assistance, and Caroline Grou and Virginie Calderon from the IRCM Bioinformatics Platform for their valuable bioinformatics support.

This work was supported by the Canadian Institutes of Health Research (CIHR) grants (PJT-159588 and PTJ-191947) and Fonds de la Recherche du Québec – Santé (FRQS) Research Scholars (Junior 2 (29106) and senior (251655)) to H.T., NIMH (R01MH077303) to G.R. and CIHR grant (PJT-180366) to E.L., an FRQS Doctoral Training scholarship (353400) and a Canadian Neurodevelopmental Research Training (CanNRT) Platform doctoral fellowship to N.C. and an IRCM Young Research scholarship and an FRQS Master’s Training scholarship (2005634) to M.W. The authors are grateful to Susan Brenner-Morton and Amy L. Norovich for kindly providing the anti-Vstm2b antibody.

Synapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada Nicolas Chofflet, Mathilde Chofflet, Mai Inagaki, Parisa Zarei, Manni Wang, Edan Shpigel, Maia Fukuyama-Kaplan, Martin Resua Rojas, Jeremie Van Prooijen, Daham Hettiarachchi, Benjamin Feller, Nayoung Yi & Hideto Takahashi Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada Nicolas Chofflet, Manni Wang & Hideto Takahashi UFR Santé, Université de Caen Normandie, Caen, France Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan Department of Pharmacology and Toxicology, Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, USA Anthony John Pastore, Shanghua Fan & Gabby Rudenko RNA Biology Research Unit, Institut de Recherches Cliniques de Montreal, Montréal, QC, Canada Department of Medicine, Université de Montréal, Montreal, QC, Canada Benjamin Feller, Nayoung Yi & Hideto Takahashi Division of Experimental Medicine, McGill University, Montreal, QC, Canada The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

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