A patient-derived mutation of epilepsy-linked LGI1 increases seizure susceptibility through regulating K v 1.1

• Published in: Cell & bioscience 2023-02, Vol.13 (1), p.34
• Main Authors: Zhou, Lin, Wang, Kang, Xu, Yuxiang, Dong, Bin-Bin, Wu, Deng-Chang, Wang, Zhao-Xiang, Wang, Xin-Tai, Cai, Xin-Yu, Yang, Jin-Tao, Zheng, Rui, Chen, Wei, Shen, Ying, Wei, Jian-She
• Format: Article
• Language: English
• ISSN: 2045-3701; 2045-3701

Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. It is known that functional LGI1 is secreted by excitatory neurons, GABAergic interneurons, and astrocytes, and regulates AMPA-type glutamate receptor-mediated synaptic transmission by binding ADAM22 and ADAM23. However, > 40 LGI1 mutations have been reported in familial ADLTE patients, more than half of which are secretion-defective. How these secretion-defective LGI1 mutations lead to epilepsy is unknown. We identified a novel secretion-defective LGI1 mutation from a Chinese ADLTE family, LGI1-W183R. We specifically expressed mutant LGI1 in excitatory neurons lacking natural LGI1, and found that this mutation downregulated K 1.1 activity, led to neuronal hyperexcitability and irregular spiking, and increased epilepsy susceptibility in mice. Further analysis revealed that restoring K 1.1 in excitatory neurons rescued the defect of spiking capacity, improved epilepsy susceptibility, and prolonged the life-span of mice. These results describe a role of secretion-defective LGI1 in maintaining neuronal excitability and reveal a new mechanism in the pathology of LGI1 mutation-related epilepsy.