NMDA receptor hypofunction on GABAergic interneurons results in input-specific Excitatory/Inhibitory imbalance in pyramidal neurons of medial prefrontal cortex

Excitation/inhibition (E/I) balance is often considered a global property of cortical circuits, although pyramidal neurons (PNs) integrate inputs from distinct afferent pathways. In a mouse model with early postnatal NMDA receptor (NMDAR) ablation in corticolimbic GABAergic interneurons, we tested whether interneuron NMDAR hypofunction disrupts mPFC E/I balance globally or in a pathway-specific manner. Combining anatomical labeling, optogenetic circuit mapping, paired recordings, and synaptic integration analysis, we found that structural and functional E/I imbalance emerged selectively at ventral hippocampal (vHPC) inputs to mPFC PNs, while callosal inputs were unaffected. Structurally, the imbalance was restricted to vHPC synapses on apical dendrites. Functionally, mutants showed an excitation-shifted E/I ratio in vHPC-driven responses due to impaired feedforward inhibition via fast-spiking interneurons, whose preferential excitatory drive from vHPC inputs was selectively lost. Short-term synaptic plasticity was unchanged, excluding altered presynaptic release dynamics as the underlying mechanism. Consistently, GABA-A receptor blockade failed to prolong vHPC-evoked EPSPs in mutant PNs, indicating loss of inhibitory control over hippocampal, but not callosal, input integration. These findings reveal a pathway-specific E/I imbalance caused by interneuron NMDAR hypofunction, suggesting selective disruption of vHPC-mPFC processing rather than global cortical dysfunction.