E4BP4-driven circadian SLC6A1 expression governs tiagabine chronoefficacy in temporal lobe epilepsy

Temporal lobe epilepsy (TLE), the most prevalent form of focal epilepsy and a leading cause of surgically managed intractable cases, is characterized by rhythmic spontaneous seizures that exhibit underutilized therapeutic potential. Here, we aim to uncover the impact of dosing time on the anticonvulsant effect of tiagabine and to elucidate the underlying mechanisms involved. Tiagabine markedly attenuated seizure severity and progression in both acute and chronic models of pilocarpine-induced TLE. Pharmacological effects of tiagabine was found to vary according to dosing time, demonstrating greater efficacy during the light phase compared to the dark phase. This variation in tiagabine efficacy was attributed to diurnal fluctuations in GABAergic neurotransmission, which depends on SLC6A1-dependent GABA reuptake rhythm. Notably, ablation of circadian transcription factor E4bp4 abolished SLC6A1 expression rhythms and abrogated the chronoefficacy of tiagabine. Our findings indicated that E4BP4-driven circadian oscillations in SLC6A1 expression regulated the efficacy of tiagabine in a circadian time-dependent manner. These results advocated for chronotherapeutic optimization of tiagabine dosing schedules to align with endogenous SLC6A1 rhythms, offering a promising avenue for precision medicine in the management of TLE.