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Epigenetic Downregulation of Scn3a Expression by Valproate: a Possible Role in Its Anticonvulsant Activity

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Abstract

Upregulation of sodium channel SCN3A expression in epileptic tissues is known to contribute to enhancing neuronal excitability and the development of epilepsy. Therefore, certain strategies to reduce SCN3A expression may be helpful for seizure control. Here, we reveal a novel role of valproate (VPA) in the epigenetic downregulation of Scn3a expression. We found that VPA, instead of carbamazepine (CBZ) and lamotrigine (LTG), could significantly downregulate Scn3a expression in mouse Neuro-2a cells. Luciferase assays and CpG methylation analyses showed that VPA induced the methylation at the -39C site in Scn3a promoter which decreased the promoter activity. We further showed that VPA downregulated the expression of methyl-CpG-binding domain protein 2 (MBD2) at the posttranscriptional level and knockdown of MBD2 increased Scn3a expression. In addition, we found that VPA induced the expression of fat mass and obesity-associated (FTO) protein and FTO knockdown abolished the repressive effects of VPA on MBD2 and Nav1.3 expressions. Furthermore, VPA, instead of other two anticonvulsant drugs, induced the expressions of Scn3a and Mbd2 and reduced Fto expression in the hippocampus of VPA-treated seizure mice. Taken together, this study suggests an epigenetic pathway for the VPA-induced downregulation of Scn3a expression, which provides a possible role of this pathway in the anticonvulsant action of VPA.

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Acknowledgments

We thank Yan Luo for helpful discussion and technical assistance. This work was supported by the National Natural Science Foundation of China (grant numbers 81371436, 31070928, 81171073, and 81471149), and partially supported by the Collaborative Innovation Center for Neurogenetics and Channelopathies. We are grateful to the He Shanheng Charity Foundation for contributing to the development of this institute.

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    1. Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, 250 Changang East Road, Guangzhou, 510260, China

      Na-Na Tan, Hui-Ling Tang, Guo-Wang Lin, Yong-Hong Chen, Ping Lu, Hai-Jun Li, Mei-Mei Gao, Qi-Hua Zhao, Yong-Hong Yi, Wei-Ping Liao & Yue-Sheng Long

    2. Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China

      Na-Na Tan, Hui-Ling Tang, Guo-Wang Lin, Yong-Hong Chen, Ping Lu, Hai-Jun Li, Mei-Mei Gao, Qi-Hua Zhao, Yong-Hong Yi, Wei-Ping Liao & Yue-Sheng Long

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    Na-Na Tan and Hui-Ling Tang contributed equally to this work.

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    Tan, NN., Tang, HL., Lin, GW. et al. Epigenetic Downregulation of Scn3a Expression by Valproate: a Possible Role in Its Anticonvulsant Activity. Mol Neurobiol 54, 2831–2842 (2017). https://doi.org/10.1007/s12035-016-9871-9

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