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

Abstract

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 LGI1W183R in excitatory neurons lacking natural LGI1, and found that this mutation downregulated Kv1.1 activity, led to neuronal hyperexcitability and irregular spiking, and increased epilepsy susceptibility in mice. Further analysis revealed that restoring Kv1.1 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.

Molecular Basis of Kv1 Channel Downregulation and Its Epileptogenic Implications in Lgi1 Knock-out Mice

“…[122 81 82] The importance of Kv2 downregulation in perturbing excitability in LGI1 deficiency is also highlighted by the fact that restoring Kv1.1 expression in secretion-deficient LGI1 W183R neurons does not fully rescue the mice life span. [22] Further investigations are needed to address whether LGI1 is directly implicated in modulating Kv2 expression levels and whether Kv1 downregulation is parallel to or consequent to Kv2 downregulation.…”

“…[21 8] An additional secretiondefective LGI1 mutation was recently found to induce Kv1.1 downregulation underlying neuronal hyperexcitability and irregular spiking in the CA1 pyramidal cells. [22] Although…”