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.
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BibTeX
@article{chofflet2026sexually,
title = {{Sexually dimorphic control of excitatory synapse maintenance in ventral hippocampal circuits by Neurexin2α ligand Vstm2b}},
author = {Nicolas Chofflet and Mathilde Chofflet and Mai Inagaki and Anthony John Pastore and Parisa Zarei and Manni Wang and Edan Shpigel and Maia Fukuyama-Kaplan and Martin Resua Rojas and Jeremie Van Prooijen and Ana Novacic and Daham Hettiarachchi and Shanghua Fan and Benjamin Feller and Nayoung Yi and Eric Lecuyer and Gabby Rudenko and Hideto Takahashi},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78199-0},
url = {https://www.nature.com/articles/s41467-026-78199-0},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Sexually dimorphic control of excitatory synapse maintenance in ventral hippocampal circuits by Neurexin2α ligand Vstm2b
AU - Nicolas Chofflet
AU - Mathilde Chofflet
AU - Mai Inagaki
AU - Anthony John Pastore
AU - Parisa Zarei
AU - Manni Wang
AU - Edan Shpigel
AU - Maia Fukuyama-Kaplan
AU - Martin Resua Rojas
AU - Jeremie Van Prooijen
AU - Ana Novacic
AU - Daham Hettiarachchi
AU - Shanghua Fan
AU - Benjamin Feller
AU - Nayoung Yi
AU - Eric Lecuyer
AU - Gabby Rudenko
AU - Hideto Takahashi
PY - 2026
DA - 2026/10/05
JO - Nature Communications
DO - 10.1038/s41467-026-78199-0
UR - https://www.nature.com/articles/s41467-026-78199-0
AB - 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.
SN - 2041-1723
ER -