Cenglin Xu1, Yi Wang1, Shuo Zhang1, Jiazhen Nao1, Yao Liu1, Ying Wang1, Fang Ding2, Kai Zhong3, Liying Chen1, Xiaoying Ying1, Shuang Wang2, Yudong Zhou1, Shumin Duan1, Zhong Chen1,2. 1. Institute of Pharmacology and Toxicology, Key Laboratory of Medical Neurobiology of National Health Commission and Chinese Academy of Medical Sciences, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China. 2. Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. 3. School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China.
Abstract
OBJECTIVE: Drug-resistant epilepsy causes great clinical danger and still lacks effective treatments. METHODS: Here, we used multifaceted approaches combining electrophysiology, optogenetics, and chemogenetics in a classic phenytoin-resistant epilepsy model to reveal the key target of subicular pyramidal neurons in phenytoin resistance. RESULTS: In vivo neural recording showed that the firing rate of pyramidal neurons in the subiculum, but not other hippocampal subregions, could not be inhibited by phenytoin in phenytoin-resistant rats. Selective inhibition of subicular pyramidal neurons by optogenetics or chemogenetics reversed phenytoin resistance, whereas selective activation of subicular pyramidal neurons induced phenytoin resistance. Moreover, long-term low-frequency stimulation at the subiculum, which is clinically feasible, significantly inhibited the subicular pyramidal neurons and reversed phenytoin resistance. Furthermore, in vitro electrophysiology revealed that off-target use of phenytoin on sodium channels of subicular pyramidal neurons was involved in the phenytoin resistance, and clinical neuroimaging data suggested the volume of the subiculum in drug-resistant patients was related to the usage of sodium channel inhibitors. INTERPRETATION: These results highlight that the subicular pyramidal neurons may be a key switch control of drug-resistant epilepsy and represent a new potential target for precise treatments. ANN NEUROL 2019;86:626-640.
OBJECTIVE:Drug-resistant epilepsy causes great clinical danger and still lacks effective treatments. METHODS: Here, we used multifaceted approaches combining electrophysiology, optogenetics, and chemogenetics in a classic phenytoin-resistant epilepsy model to reveal the key target of subicular pyramidal neurons in phenytoin resistance. RESULTS: In vivo neural recording showed that the firing rate of pyramidal neurons in the subiculum, but not other hippocampal subregions, could not be inhibited by phenytoin in phenytoin-resistant rats. Selective inhibition of subicular pyramidal neurons by optogenetics or chemogenetics reversed phenytoin resistance, whereas selective activation of subicular pyramidal neurons induced phenytoin resistance. Moreover, long-term low-frequency stimulation at the subiculum, which is clinically feasible, significantly inhibited the subicular pyramidal neurons and reversed phenytoin resistance. Furthermore, in vitro electrophysiology revealed that off-target use of phenytoin on sodium channels of subicular pyramidal neurons was involved in the phenytoin resistance, and clinical neuroimaging data suggested the volume of the subiculum in drug-resistant patients was related to the usage of sodium channel inhibitors. INTERPRETATION: These results highlight that the subicular pyramidal neurons may be a key switch control of drug-resistant epilepsy and represent a new potential target for precise treatments. ANN NEUROL 2019;86:626-640.