Abstract
BACKGROUND: Interictal cognitive and affective comorbidities in temporal lobe epilepsy (TLE) often remain refractory to seizure-directed therapies. We tested the causal role of ventral hippocampal CA1/subiculum (vCA1/Sub) hyperexcitability in social memory failure and anxiety-related behavior, and whether normalizing principal-cell excitability restores function. METHODS: In pilocarpine-treated mice we combined blinded behavioral assays (social approach/discrimination, open field, olfaction), whole-cell recordings from mCherry-labeled vCA1/Sub principal neurons, alveus stimulation to assay synaptic inhibition/excitation, immunohistochemistry for parvalbumin (PV) and somatostatin (SST) interneurons, and chemogenetic control of excitability (hM3Dq in controls; hM4Di and KORD in epileptic mice). Missing behavioral outcomes were handled by multiple imputation with bootstrapping; pooled analyses used ANOVA, mixed-effects models, and logistic regression. RESULTS: Epileptic mice showed preserved social approach but impaired social discrimination, with intact detection of social odors. Regular-spiking and bursting vCA1/Sub neurons exhibited depolarized resting membrane potential and reduced synaptically driven hyperpolarizations during alveus stimulation, indicating disinhibition; PV and SST interneuron densities were reduced in stratum oriens. Chemogenetic manipulation bidirectionally tuned excitability: bath CNO depolarized hM3Dq-expressing cells, whereas it hyperpolarized hM4Di-expressing cells by ~5 mV and decreased current-evoked spiking. In vivo, inhibiting vCA1/Sub principal cells (hM4Di or KORD activation) increased the probability of successful social discrimination in epileptic mice without altering investigation time; neither CNO nor salvinorin B affected unDREADDed animals. In the open field, epileptic mice displayed reduced center preference and high-velocity bouts; vCA1/Sub inhibition normalized center preference and movement toward control values. Center preference predicted social discrimination in DREADDed epileptic mice, linking anxiety-related behavior to vCA1/Sub excitability. CONCLUSIONS: vCA1/Sub hyperexcitability drives interictal social memory and anxiety-related deficits in chronic TLE. Reducing principal-cell excitability restores behavior despite interneuron loss, supporting a model in which ventral hippocampal output can be retuned to rescue cognition. These results nominate neuromodulation of vCA1/Sub as a strategy to improve quality of life in epilepsy.