The KCC2 Cotransporter and Human Epilepsy Getting Excited About Inhibition

摘要: The cation-Cl- cotransporter KCC2, encoded by SLC12A5, is required for the emergence and maintenance of GABAergic fast synaptic inhibition in organisms across evolution. These findings have suggested that KCC2 deficiency might play a role pathogenesis human epilepsy, but this has only recently been substantiated two lines genetic evidence. first discovery heterozygous missense polymorphisms causing decreased KCC2-dependent Cl- extrusion capacity, an Australian family with inherited febrile seizures French-Canadian cohort severe generalized epilepsy (GGE). second recessive loss-of-function mutations SLC12A5 patients severe, early-onset Mendelian disease termed "epilepsy infancy migrating focal seizures" (EIMFS). collectively support paradigm precisely regulated activity humans, genetically impairment function, due to effects on gene dosage, intrinsic activity, or extrinsic regulation, can influence phenotypes patients. Accordingly, could be target novel antiepileptic strategies aims restore GABA facilitating extrusion. Such drugs relevance pharmaco-resistant epilepsies possibly other diseases characterized hyperexcitability, such as spectrum autism disorders.