Retuning ventral hippocampal output improves social memory and reduces anxiety-related behavior in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is associated with cognitive, social, and emotional comorbidities that persist between seizures and remain poorly addressed by seizure-focused treatment. We examined whether these interictal deficits reflect altered ventral CA1/subiculum (vCA1/Sub) output and whether shifting principal-cell excitability can improve behavior despite persistent pathology. In pilocarpine-treated mice, vCA1/Sub principal neurons were depolarized and showed altered recruitment, alveus/oriens stimulation produced diminished hyperpolarizing responses, and parvalbumin- and somatostatin-immunopositive cell densities were reduced in stratum oriens. Epileptic mice did not demonstrate social discrimination above chance despite retained social approach and social-odor preference and showed increased open-field center avoidance. Multiplexed chemogenetic inhibition of vCA1/Sub principal cells improved social discrimination and center exploration, whereas stronger inhibition did not reproduce the social-memory benefit. Within individual mice, discrimination was higher in predicted retuned than off-optimal states, and performance across inferred excitability states followed an inverted-U-like relationship. Anxiety-related and social improvements covaried across epileptic mice, consistent with shared dependence on vCA1/Sub circuit state. In a separate EEG cohort, moderate inhibition suppressed local hippocampal activity during the behavior-aligned interval without detectably reducing spontaneous seizures or early interictal spikes. These findings identify excessive vCA1/Sub output as a modifiable contributor to socio-affective dysfunction in TLE and show that retuning a disease-altered circuit can improve interictal behavior without acute seizure suppression.