A patient-derived mutation of epilepsy-linked LGI1 increases seizure susceptibility through regulating K_v1.1

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^W183R in excitatory neurons lacking natural LGI1, and found that this mutation downregulated K_v1.1 activity, led to neuronal hyperexcitability and irregular spiking, and increased epilepsy susceptibility in mice. Further analysis revealed that restoring K_v1.1 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.