2. Academic Validation
  3. TRESK channel contributes to depolarization-induced shunting inhibition and modulates epileptic seizures

TRESK channel contributes to depolarization-induced shunting inhibition and modulates epileptic seizures

  • Cell Rep. 2021 Jul 20;36(3):109404. doi: 10.1016/j.celrep.2021.109404.
Weiyuan Huang 1,  Yue Ke 1,  Jianping Zhu 1,  Shuai Liu 1,  Jin Cong 1,  Hailin Ye 1,  Yanwu Guo 2,  Kewan Wang 3,  Zhenhai Zhang 4,  Wenxiang Meng 5,  Tian-Ming Gao 6,  Heiko J Luhmann 7,  Werner Kilb 8,  Rongqing Chen 9
Affiliations

Affiliations

  • 1 Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2 The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
  • 3 Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 4 State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Center for Precision Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510030, China; Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou 510515, China.
  • 5 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
  • 6 Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou 510515, China; State Key Laboratory of Organ Failure Research, Collaborative Innovation Center for Brain Science, Southern Medical University, Guangzhou 510515, China.
  • 7 Institute of Physiology, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, Mainz 55120, Germany.
  • 8 Institute of Physiology, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, Mainz 55120, Germany. Electronic address: [email protected].
  • 9 Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
PMID: 34289346 DOI: 10.1016/j.celrep.2021.109404
Abstract

Glutamatergic and GABAergic synaptic transmission controls excitation and inhibition of postsynaptic neurons, whereas activity of ion channels modulates neuronal intrinsic excitability. However, it is unclear how excessive neuronal excitation affects intrinsic inhibition to regain homeostatic stability under physiological or pathophysiological conditions. Here, we report that a seizure-like sustained depolarization can induce short-term inhibition of hippocampal CA3 neurons via a mechanism of membrane shunting. This depolarization-induced shunting inhibition (DShI) mediates a non-synaptic, but neuronal intrinsic, short-term plasticity that is able to suppress action potential generation and postsynaptic responses by activated ionotropic receptors. We demonstrate that the TRESK channel significantly contributes to DShI. Disruption of DShI by genetic knockout of TRESK exacerbates the sensitivity and severity of epileptic seizures of mice, whereas overexpression of TRESK attenuates seizures. In summary, these results uncover a type of homeostatic intrinsic plasticity and its underlying mechanism. TRESK might represent a therapeutic target for antiepileptic drugs.

Keywords

K2P channels; TRESK channel; epilepsy; postictal depression; seizure; seizure termination; short-term plasticity; shunting inhibition.

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