摘要Cholinergic transmission,independent of classical glutamatergic and GABAergic signaling,critically plays a crucial role in epilepsy.Huperzine A(Hup A),an acetylcholinesterase(AChE)inhibitor,exerts potent anticonvulsant activity,but its mechanism of action within cholinergic circuits remains unclear.Here,we show that Hup A mitigates epileptic seizures by enhancing hippocampal dorsal CA1(dCA1)-projecting cholinergic transmission.We found that systemic injection of Hup A not only reduces seizures in acute models,including the maximal-electroshock seizure(MES),pentylenetetrazol(PTZ),and kainic acid(KA)models but also alleviates the seizure severity in chronic epilepsy models induced by kindling and KA,indicating a broad-spectrum anti-seizure efficacy.Interestingly,using immunohistochemistry,viral tracing,and in vivo fiber photometry,we found that Hup A selectively inhibits AChE in the dCA1 rather than in other hippocampal subregions or cortex,enhancing dCA1-projecting septal cholinergic transmission.Significantly,selective ablation of septal ChAT+neurons reversed the anti-seizure effects of Hup A.We further identified that α7 nicotinic acetylcholine receptors in the dCA1 region mediate the anti-seizures cholinergic circuit modulated by Hup A.Together,our results demonstrate that Hup A exerts broad-spectrum anti-seizure efficacy via modulating dCA1-projecting septal cholinergic transmission,providing potential therapeutic avenues for epilepsy through targeted cholinergic modulation.