title: Hyperexcitability and epilepsy associated with disruption of the mouse neuronal-specific K-Cl cotransporter gene.
abstract: Four genes encode electroneutral, Na+-independent, K-Cl cotransporters. KCC2, is exclusively expressed in neurons where it is thought to drive intracellular Cl- to low concentrations and shift the reversal potential for Cl- conductances such as GABA(A) or glycine receptor channels, thus participating in the postnatal development of inhibitory mechanisms in the brain. Indeed, expression of the cotransporter is low at birth and increases postnatally, at a time when the intracellular Cl- concentration in neurons decreases and gamma-aminobutyric acid switches its effect from excitatory to inhibitory. To assert the significance of KCC2 in neuronal function, we disrupted the mouse gene encoding this neuronal-specific K-Cl cotransporter. We demonstrate that animals deficient in KCC2 exhibit frequent generalized seizures and die shortly after birth. We also show upregulation of Fos, the product of the immediate early gene c-fos, and the significant loss of parvalbumin-positive interneurons, both indicative of brain injury. The regions most affected are the hippocampus and temporal and entorhinal cortices. Extracellular field potential measurements in the CA1 hippocampus exhibited hyperexcitability. Application of picrotoxin, a blocker of the GABA(A) receptor, further increased hyperexcitability in homozygous hippocampal sections. Pharmacological treatment of pups showed that diazepam relieved the seizures while phenytoin prevented them between postnatal ages P4-P12. Finally, we demonstrate that adult heterozygote animals show increased susceptibility for epileptic seizure and increased resistance to the anticonvulsant effect of propofol. Taken together, these results indicate that KCC2 plays an important role in controlling CNS excitability during both postnatal development and adult life.
authors: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2520, USA.
authors: Nam-Sik
authors: NS
authors: Woo
authors: Jianming
authors: J
authors: Lu
authors: Roger
authors: R
authors: England
authors: Robert
authors: R
authors: McClellan
authors: Samuel
authors: S
authors: Dufour
authors: David B
authors: DB
authors: Mount
authors: Ariel Y
authors: AY
authors: Deutch
authors: David M
authors: DM
authors: Lovinger
authors: Eric
authors: E
authors: Delpire
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002678:Chimera; D003292:Convulsants; D018728:Entorhinal Cortex / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D005260:Female; D006579:Heterozygote; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development / Q000502:physiology*; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000502:physiology*; D010433:Pentylenetetrazole; D015742:Propofol / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D027981:Symporters / Q000235:genetics* / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D000096922:K Cl- Cotransporters
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D010433:Pentylenetetrazole; D015742:Propofol; D016760:Proto-Oncogene Proteins c-fos; D027981:Symporters; D000096922:K Cl- Cotransporters