title: Entorhinal Principal Neurons Mediate Brain-stimulation Treatments for Epilepsy.
abstract: Brain stimulation is an alternative treatment for epilepsy. However, the neuronal circuits underlying its mechanisms remain obscure. We found that optogenetic activation (1Hz) of entorhinal calcium/calmodulin-dependent protein kinase II α (CaMKIIα)-positive neurons, but not GABAergic neurons, retarded hippocampal epileptogenesis and reduced hippocampal seizure severity, similar to that of entorhinal low-frequency electrical stimulation (LFES). Optogenetic inhibition of entorhinal CaMKIIα-positive neurons blocked the antiepileptic effect of LFES. The channelrhodopsin-2-eYFP labeled entorhinal CaMKIIα-positive neurons primarily targeted the hippocampus, and the activation of these fibers reduced hippocampal seizure severity. By combining extracellular recording and pharmacological methods, we found that activating entorhinal CaMKIIα-positive neurons induced the GABA-mediated inhibition of hippocampal neurons. Optogenetic activation of focal hippocampal GABAergic neurons mimicked this neuronal modulatory effect and reduced hippocampal seizure severity, but the anti-epileptic effect is weaker than that of entorhinal LFES, which may be due to the limited spatial neuronal modulatory effect of focal photo-stimulation. Our results demonstrate a glutamatergic-GABAergic neuronal circuit for LFES treatment of epilepsy, which is mediated by entorhinal principal neurons.
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
authors.forename: Zhenghao
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Cenglin
authors.initials: C
authors.lastname: Xu
authors.affiliation: Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Shihong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Xiangnan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Shumin
authors.initials: S
authors.lastname: Duan
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China; Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Electronic address: chenzhong@zju.edu.cn.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D046690:Deep Brain Stimulation; D004195:Disease Models, Animal; D018728:Entorhinal Cortex / Q000378:metabolism* / Q000503:physiopathology*; D004827:Epilepsy / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy*; D059330:GABAergic Neurons / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: C529569:CAMK2N1 protein, human; D011506:Proteins
keywords: Brain stimulation; Entorhinal cortex; Epilepsy; Kindling; Neuronal circuit; Optogenetics