Neuroligin-2-Dependent Adhesion Defines a Molecular Checkpoint for Inhibitory Synaptic Plasticity

Abstract

Long-term regulation of inhibitory synaptic strength is crucial for maintaining excitation–inhibition (E/I) balance in cortical circuits. In this study, we identify neuroligin-2 (Nlgn2) as a critical mediator of inhibitory long-term potentiation (iLTP) in hippocampal CA1 pyramidal cells (PCs). Using neurolide-2, a synthetic dendrimeric peptide that selectively interferes with Nlgn2–neurexin binding, in combination with whole-cell recordings in mouse hippocampal slices, we show that this interaction is required to maintain NMDA-induced iLTP. Disruption of Nlgn2–neurexin interactions blocked gephyrin clustering during iLTP and prevented Nlgn2 recruitment to GABAergic synapses, without affecting baseline inhibitory transmission. Immunostaining revealed that NMDA-induced enlargement of synaptic Nlgn2 clusters occurred selectively in the CA1 stratum oriens and was abolished by neurolide-2. Temporally controlled peptide application revealed a brief, 10 min post-induction window during which Nlgn2–neurexin adhesion is required for iLTP consolidation, and later application had no effect. Optogenetic experiments further demonstrated that NMDA-induced iLTP at both somatostatin (SST) and parvalbumin (PV) inputs depends on Nlgn2. In a more physiological paradigm, high-frequency stimulation of excitatory inputs paired with postsynaptic CA1 PC depolarization triggered heterosynaptic iLTP selectively at SST → PC synapses, which was unaffected during induction but failed to consolidate when Nlgn2–neurexin interaction was blocked, whereas excitatory LTP and PV-mediated inhibition remained intact. These findings identify perisynaptic Nlgn2–neurexin adhesion as an activity-dependent mechanism supporting inhibitory plasticity depending on input identity and induction protocol. Disruption of this process may impair inhibitory circuit remodeling, contributing to E/I imbalance in neurodevelopmental and psychiatric disorders.