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Knockdown of SIK3 in the CA1 Region can Reduce Seizure Susceptibility in Mice by Inhibiting Decreases in GABAAR α1 Expression

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Abstract

Imbalance between excitation and inhibition is an important cause of epilepsy. Salt-inducible kinase 1 (SIK1) gene mutation can cause epilepsy. In this study, we first found that the expression of SIK3 is increased after epilepsy. Furthermore, the role of SIK3 in epilepsy was explored. In cultured hippocampal neurons, we used Pterosin B, a selective SIK3 inhibitor that can inhibit epileptiform discharges induced by the convulsant drug cyclothiazide (a positive allosteric modulator of AMPA receptors, CTZ). Knockdown of SIK3 inhibited epileptiform discharges and increased the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). In mice, knockdown of SIK3 reduced epilepsy susceptibility in a pentylenetetrazole (a GABAA receptor antagonist, PTZ) acute kindling experiment and increased the expression of GABAA receptor α1. In conclusion, our results suggest that blockade or knockdown of SIK3 can inhibit epileptiform discharges and that SIK3 has the potential to be a novel target for epilepsy treatment.

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Data Availability

The data and materials used or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank Hanbio Co. Ltd. (Shanghai, China) for providing the AAV for this research.

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Authors and Affiliations

  1. Dalian Medical University, Dalian, 116044, Liaoning, China

    Zhen-Fu Jiang, Li-Na Xuan, Shao-Bo Liu & Jian Yin

  2. Department of Neurosurgery, the Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Shahekou, Dalian, 116023, Liaoning, China

    Zhen-Fu Jiang & Jian Yin

  3. East China Normal University, Shanghai, 200241, China

    Xiao-Wan Sun

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Jian Yin designed the study. Zhen-fu Jiang and Li-Na Xuan performed the experiments. Xiao-Wan Sun and Shao-Bo Liu analyzed the data. Zhen-fu Jiang wrote the manuscript. Jian Yin critically edited the manuscript.

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Jiang, ZF., Xuan, LN., Sun, XW. et al. Knockdown of SIK3 in the CA1 Region can Reduce Seizure Susceptibility in Mice by Inhibiting Decreases in GABAAR α1 Expression. Mol Neurobiol 61, 1404–1416 (2024). https://doi.org/10.1007/s12035-023-03630-2

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