NMDA-dependent coplasticity in VIP interneuron-driven inhibitory circuits

Abstract 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 kinetics in FS interneurons compared to 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 E/I balance within local hippocampal circuits.