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Genetic Knockout of TRPM2 Increases Neuronal Excitability of Hippocampal Neurons by Inhibiting Kv7 Channel in Epilepsy

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Abstract

Epilepsy is a chronic brain disease that makes serious cognitive and motor retardation. Ion channels affect the occurrence of epilepsy in various ways, but the mechanisms have not yet been fully elucidated. Transient receptor potential melastain2 (TRPM2) ion channel is a non-selective cationic channel that can permeate Ca2+ and critical for epilepsy. Here, TRPM2 gene knockout mice were used to generate a chronic kindling epilepsy model by PTZ administration in mice. We found that TRPM2 knockout mice were more susceptible to epilepsy than WT mice. Furthermore, the neuronal excitability in the hippocampal CA1 region of TRPM2 knockout mice was significantly increased. Compared with WT group, there were no significant differences in the input resistance and after hyperpolarization of CA1 neurons in TRPM2 knockout mice. Firing adaptation rate of hippocampal CA1 pyramidal neurons of TRPM2 knockout mice was lower than that of WT mice. We also found that activation of Kv7 channel by retigabine reduced the firing frequency of action potential in the hippocampal pyramidal neurons of TRPM2 knockout mice. However, inhibiting Kv7 channel increased the firing frequency of action potential in hippocampal pyramidal neurons of WT mice. The data suggest that activation of Kv7 channel can effectively reduce epileptic seizures in TRPM2 knockout mice. We conclude that genetic knockout of TRPM2 in hippocampal CA1 pyramidal neurons may increase neuronal excitability by inhibiting Kv7 channel, affecting the susceptibility to epilepsy. These findings may provide a potential therapeutic target for epilepsy.

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Data Availability

The datasets used during the present study are available from the corresponding author upon reasonable request.

Abbreviations

AP:

Action potential

CNS:

Central nervous system

Kv7:

KCNQ-encoded voltage-dependent K+ channels

mAHP:

Medium after hyperpolarization

M current:

Kv7 current

PTZ:

Pentylenetetrazole

RMP:

Resting membrane potential

R in :

Input resistance

ROS:

Reactive oxygen species

sEPSC:

Spontaneous excitatory postsynaptic current

TRPM2:

Transient receptor potential melastain2

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Acknowledgements

The TRPM2 KO mice were kindly provided by Prof. Fang Xiangming from Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Japan. We are grateful to Prof. Zhou Yudong who helped us to successfully complete this research work.

Funding

This work was supported by Grants from the National Natural Science Foundation of China (Nos. 82171438, 81671287, 81372116, 81201511), Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents, and Zhejiang Province Public Welfare Technology Application Research Project (Nos. LY22H090005, LY15H090006).

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  1. Yingchao Ying and Lifen Gong have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China

    Yingchao Ying, Lifen Gong, Xiaohan Tao, Junchao Ding, Nannan Chen, Yinping Yao, Jiajing Liu, Chen Chen & Peifang Jiang

  2. Department of Pediatrics, Yiwu Maternal and Child Health Care Hospital, Yiwu, China

    Junchao Ding

  3. Department of Pediatrics, Shaoxing People’s Hospital, Shaoxing, China

    Yinping Yao

  4. Department of Critical Care Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    Tao Zhu

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Contributions

Peifang Jiang and Tao Zhu designed the experiments. Yingchao Ying, Lifen Gong, and Chen Chen performed the experiments. Yingchao Ying and Peifang Jiang analyzed and wrote the manuscript. Other authors helped perform the experiments. All authors contributed to the article and approved the submitted version.

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Correspondence to Tao Zhu or Peifang Jiang.

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The animal study was reviewed and approved by the Animal Experiment Ethics Committee of Zhejiang University.

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Ying, Y., Gong, L., Tao, X. et al. Genetic Knockout of TRPM2 Increases Neuronal Excitability of Hippocampal Neurons by Inhibiting Kv7 Channel in Epilepsy. Mol Neurobiol 59, 6918–6933 (2022). https://doi.org/10.1007/s12035-022-02993-2

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