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 (soINs) 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 → soIN synapses in two distinct soIN subtypes: fast-spiking (FS) and oriens-lacunosum moleculare (OLM)/bistratified interneurons. Optogenetically evoked VIP → soIN 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 soINs demonstrated NMDA-induced long-term potentiation (E → I LTP) after brief NMDA exposure but not after prolonged application. Notably, coplasticity analysis in individual soINs 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.