Differential circadian time modulates of dentate gyrus and CA1 excitation-inhibition balance and seizure threshold

Abstract Circadian rhythms regulate seizure threshold and neuronal excitability in epilepsy. Temporal lobe seizures tend to arise more frequently during the diurnal phase relative to the nocturnal phase, yet dentate gyrus (DG) granule cells display elevated intrinsic excitability and CA1 pyramidal neurons show enhanced synaptic excitability at night. Here, we used male adult ICR mice (8–10 weeks old) as experimental subjects. Systemic pilocarpine injection was applied to pharmacologically trigger acute seizures, while AAV (pAAV2/9-CaMKIIα-hChR2 (H134R) - EYFP) delivery followed by optogenetic stimulation (10 Hz, 20 ms pulse width, 5 mW 473 nm blue light) was implemented to evoke region-specific hippocampal seizures. Combining continuous video-electroencephalography (vEEG) recording, optogenetically induced seizure assays, mRNA sequencing, and whole-cell patch-clamp electrophysiology, we investigated circadian modulation of neuronal excitability and seizure threshold within the DG and CA1 subfields of the hippocampus. Our results revealed divergent circadian regulation of seizure thresholds between the DG and CA1 regions. Notably, the diurnal-nocturnal seizure threshold pattern in CA1 recapitulated that seen in systemic pilocarpien-provoked seizure models. We further confirmed that circadian cycles exert distinct regulatory effects on excitatory/inhibitory synaptic transmission and the intrinsic excitability of hippocampal principal neurons in the DG and CA1. Collectively, this work highlights region-specific circadian control over seizure susceptibility and the brain excitation-inhibition balance. Elucidating circadian influences on hippocampal physiology and seizure threshold will improve the translational value of anti-epileptic therapies and guide time-stratified seizure intervention strategies.