Hyperexcitability and epilepsy associated with disruption of the mouse neuronal-specific K–Cl cotransporter gene
Article first published online: 25 FEB 2002
Copyright © 2002 Wiley-Liss, Inc.
Volume 12, Issue 2, pages 258–268, 2002
How to Cite
Woo, N.-S., Lu, J., England, R., McClellan, R., Dufour, S., Mount, D. B., Deutch, A. Y., Lovinger, D. M. and Delpire, E. (2002), Hyperexcitability and epilepsy associated with disruption of the mouse neuronal-specific K–Cl cotransporter gene. Hippocampus, 12: 258–268. doi: 10.1002/hipo.10014
- Issue published online: 25 FEB 2002
- Article first published online: 25 FEB 2002
- Manuscript Accepted: 24 AUG 2001
- National Institutes of Health. Grant Numbers: R01 NS36758, RO1 DK57708, R01 MH57995, R01 AA08986
- Veterans Administration/Advanced Research Career Development Award
- synaptic transmission;
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 GABAA 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 γ-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 GABAA 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. Hippocampus 2002;12:258–268. © 2002 Wiley-Liss, Inc.