NEDD4-2 and the CLC-2 channel regulate neuronal excitability in the pathogenesis of mesial temporal lobe epilepsy

• Published in: Scientific reports Vol. 14; no. 1; pp. 4835 - 10
• Main Authors: Liu, Yuting, Yang, Haiyan, Zeng, Rongrong, He, Lu, Xiao, Ting, Peng, Xiaomei, Kuang, Zhuo, Wu, Liwen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.02.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/378; 631/80; Cell culture; Epilepsy; Excitability; Hippocampus; Humanities and Social Sciences; Lithium; Magnesium; multidisciplinary; Pathogenesis; Pilocarpine; Science; Science (multidisciplinary); Temporal lobe
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-52399-4

An increasing number of studies have focused on the role of NEDD4-2 in regulating neuronal excitability and the mechanism of epilepsy. However, the exact mechanism has not yet been elucidated. Here, we explored the roles of NEDD4-2 and the CLC-2 channel in regulating neuronal excitability and mesial temporal lobe epilepsy (MTLE) pathogenesis. First, chronic MTLE models were induced by lithium-pilocarpine in developmental rats. Coimmunoprecipitation analysis revealed that the interaction between CLC-2 and NEDD4-2 . Western blot analyses indicated that NEDD4-2 expression was downregulated, while phosphorylated (P-) NEDD4-2 and CLC-2 expression was upregulated in adult MTLE rats. Then, the primary hippocampal neuronal cells were isolated and cultured, and the NEDD4-2 was knocked down by shRNA vector, resulting in decreased protein levels of CLC-2. While CLC-2 absence caused increased NEDD4-2 in cells. Next, in an epileptic cell model induced by a Mg 2+ -free culture, whole-cell current-clamp recording demonstrated that NEDD4-2 deficiency inhibited the spontaneous action potentials of cells, and CLC-2 absence caused more significant decrease in the spontaneous action potentials of cells. In conclusion, we herein revealed that NEDD4-2 regulates the expression of CLC-2, which is involved in neuronal excitability, and participates in the pathogenesis of MTLE.