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Here, we investigated how dorsal raphe (DR) and its 5\u2010HTergic neurons are implicated in epilepsy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In mouse hippocampal kindling model, using immunochemistry, calcium fiber photometry, and optogenetics, we investigated the causal role of DR 5\u2010HTergic neurons in seizure of temporal lobe epilepsy (TLE). Further, deep brain stimulation (DBS) of the DR with different frequencies was applied to test its effect on hippocampal seizure and depressive\u2010like behavior.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Number of c\u2010fos<jats:sup>+<\/jats:sup> neurons in the DR and calcium activities of DR 5\u2010HTergic neurons were both increased during kindling\u2010induced hippocampal seizures. Optogenetic inhibition, but not activation, of DR 5\u2010HTergic neurons conspicuously retarded seizure acquisition specially during the late period. For clinical translation, 1\u2010Hz\u2010specific, but not 20\u2010Hz or 100\u2010Hz, DBS of the DR retarded the acquisition of hippocampal seizure. This therapeutic effect may be mediated by the inhibition of DR 5\u2010HTergic neurons, as optogenetic activation of DR 5\u2010HTergic neurons reversed the anti\u2010seizure effects of 1\u2010Hz DR DBS. However, DBS treatment had no effect on depressive\u2010like behavior.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Inhibition of hyperactivity of DR 5\u2010HTergic neuron may present promising anti\u2010seizure effect and the DR may be a potential DBS target for the therapy of TLE.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.13648","type":"journal-article","created":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T05:24:47Z","timestamp":1620365087000},"page":"963-972","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Inhibition of hyperactivity of the dorsal raphe 5\u2010HTergic neurons ameliorates hippocampal seizure"],"prefix":"10.1111","volume":"27","author":[{"given":"Heming","family":"Cheng","sequence":"first","affiliation":[{"name":"Institute of Pharmacology &amp; Toxicology College of Pharmaceutical Sciences Zhejiang University  Hangzhou 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