NMDA ‐Dependent Coplasticity in VIP Interneuron‐Driven Inhibitory Circuits

Inhibitory plasticity is emerging as a key regulator of excitation/inhibition (E/I) balance, a fundamental determinant of brain network dynamics. While significant progress has been made in understanding inhibitory plasticity at synapses targeting excitatory principal neurons (I → E), the mechanisms and functional implications of plasticity at interneuron‐interneuron (I → I) synapses remain largely unexplored. Herein, we investigated the properties and plasticity of inhibitory inputs from vasoactive intestinal peptide (VIP) interneurons onto stratum oriens interneurons ( so INs) in the hippocampal CA1 region. Using optogenetics, patch‐clamp electrophysiology, and morphological reconstructions, we characterized the kinetics, short‐term plasticity, and NMDA receptor‐dependent long‐term plasticity at VIP →  so IN synapses in two distinct so IN subtypes: fast‐spiking (FS) and oriens‐lacunosum moleculare (OLM)/bistratified interneurons. Optogenetically evoked VIP →  so IN IPSCs showed faster rise times and slower decay in FS interneurons than in OLM/bistratified cells, although both subtypes exhibited similar short‐term plasticity profiles. Brief NMDA receptor activation (1 min) induced long‐term depression (iLTD) at VIP → OLM/bistratified synapses but not at VIP → FS synapses, underscoring subtype‐specific plasticity. However, prolonged NMDA exposure (2 min) elicited iLTD in both interneuron subtypes. Interestingly, excitatory inputs to so INs demonstrated NMDA‐induced long‐term potentiation (E → I LTP) after brief NMDA exposure but not after prolonged application. Notably, coplasticity analysis in individual so INs revealed asymmetric co‐expression of I → I LTD and E → I LTP in OLM/bistratified interneurons. In contrast, FS interneurons exhibited a duration‐dependent transition between asymmetric and symmetric coplasticity. These findings reveal a target cell‐specific landscape of inhibitory I → I plasticity and its co‐expression with excitatory plasticity, highlighting VIP interneurons as key modulators of the E/I balance within local hippocampal circuits. image