Neuroligin-2–dependent adhesion defines a molecular checkpoint for inhibitory synaptic plasticity

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 mice 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 effecting 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-minute 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.<b>Significance Statement</b> The brain remains flexible and learns by adjusting the strength of excitatory and inhibitory synapses. While excitatory plasticity is well characterized, the rules guiding the induction and consolidation of inhibitory plasticity are less clear. We found that neuroligin-2, an adhesion protein that organizes inhibitory synapse formation, is also essential for inhibitory plasticity in the hippocampus, a brain region important for memory. Moreover, interference with neuroligin-2-dependent adhesion can erase already developed inhibitory plasticity within a short time window after induction, without affecting simultaneous plastic changes at excitatory synapses. These results highlight the consolidation phase of inhibitory plasticity and identify a mechanism that, if disturbed, may contribute to epilepsy, autism, and schizophrenia, which are linked to neuroligin-2 dysfunction.