title: The KCC2 Cotransporter and Human Epilepsy: Getting Excited About Inhibition.
abstract: 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 in the pathogenesis human epilepsy, but this has only recently been substantiated by two lines of genetic evidence. The first is the discovery of heterozygous missense polymorphisms in SLC12A5, causing decreased KCC2-dependent Cl-extrusion capacity, in an Australian family with inherited febrile seizures and in a French-Canadian cohort with severe genetic generalized epilepsy (GGE). The second is the discovery of recessive loss-of-function mutations in SLC12A5 in patients with a severe, early-onset Mendelian disease termed "epilepsy of infancy with migrating focal seizures" (EIMFS). These findings collectively support the paradigm that precisely regulated KCC2 activity is required for synaptic inhibition in humans, and that genetically encoded impairment of KCC2 function, due to effects on gene dosage, intrinsic activity, or extrinsic regulation, can influence epilepsy phenotypes in patients. Accordingly, KCC2 could be a target for a novel antiepileptic strategies that aims to restore GABA inhibition by facilitating Cl-extrusion. Such drugs could have relevance for pharmaco-resistant epilepsies and possibly other diseases characterized by synaptic hyperexcitability, such as the spectrum autism disorders.
authors.affiliation: Departments of Neurosurgery, Pediatrics, and Cellular and Molecular Physiology, Yale Program in Neurogenetics, and Centers for Mendelian Genomics, Yale University School of Medicine, New Haven, CT, USA kristopher.kahle@yale.edu.
authors.forename: Kristopher T
authors.initials: KT
authors.lastname: Kahle
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Arjun R
authors.initials: AR
authors.lastname: Khanna
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: JingJing
authors.initials: J
authors.lastname: Duan
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Staley
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Delpire
authors.affiliation: Division of Epilepsy and Clinical Electrophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Annapurna
authors.initials: A
authors.lastname: Poduri
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D004827:Epilepsy / Q000235:genetics* / Q000628:therapy; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation / Q000235:genetics*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D000927:Anticonvulsants; D028021:Sodium-Potassium-Chloride Symporters; D027981:Symporters; D000096922:K Cl- Cotransporters; C415467:SLC12A9 protein, human
keywords: KCC2; antiepileptic therapy; cation-chloride cotransport; epilepsy; neurogenetics