A patient-derived mutation of epilepsy-linked LGI1 increases seizure susceptibility through regulating Kv1.1

• Published in: Cell & bioscience Vol. 13; no. 1; pp. 1 - 18
• 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: Journal Article
• Language: English
• Published: London BioMed Central 20.02.2023; BioMed Central Ltd; BMC
• Subjects: ADLTE; Analysis; Antibodies; Astrocytes; Biomedical and Life Sciences; Cell Biology; Computer simulation; Convulsions & seizures; Epilepsy; Ethylenediaminetetraacetic acid; Excitability; GABA; Genetic aspects; Glioma; Glutamate; Glutamic acid receptors; Interneurons; Leucine-rich glioma inactivated 1; LGI1 protein; Life Sciences; Microbiology; Mutation; Nervous system; Neurobiology; Neurons; Potassium channels (voltage-gated); Precision medicine; Proteins; Proteomics; Reagents; Secretion; Seizures; Seizures (Medicine); Stem Cells; Synaptic transmission; Tinnitus; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; γ-Aminobutyric acid; Leucine-rich glioma inactivated 1; Precision medicine; Epilepsy; ADLTE
• ISSN: 2045-3701; 2045-3701
• DOI: 10.1186/s13578-023-00983-y

Background 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. Results We identified a novel secretion-defective LGI1 mutation from a Chinese ADLTE family, LGI1-W183R. We specifically expressed mutant LGI1 W183R in excitatory neurons lacking natural LGI1, and found that this mutation downregulated K v 1.1 activity, led to neuronal hyperexcitability and irregular spiking, and increased epilepsy susceptibility in mice. Further analysis revealed that restoring K v 1.1 in excitatory neurons rescued the defect of spiking capacity, improved epilepsy susceptibility, and prolonged the life-span of mice. Conclusions 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.