ArticlebioRxiv : the preprint server for biology2025
Reducing ventral hippocampal CA1/subiculum hyperexcitability restores social memory and alleviates anxiety-related behavior in a mouse model of temporal lobe epilepsy.
Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Excitability-margin narrowing as a candidate gating mechanism for maladaptive circuit reactivation: a ventral CA1-centered model.Frontiers in behavioral neuroscience · 2026Article
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6 authors.
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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.
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Registered trials
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