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Mice with a targeted disruption of the Cl-/HCO3- exchanger AE3 display a reduced seizure threshold

Item Type:Article
Title:Mice with a targeted disruption of the Cl-/HCO3- exchanger AE3 display a reduced seizure threshold
Creators Name:Hentschke, M., Wiemann, M., Hentschke, S., Kurth, I., Hermans-Borgmeyer, I., Seidenbecher, T., Jentsch, T.J., Gal, A. and Huebner, C.A.
Abstract:Neuronal activity results in significant pH shifts in neurons, glia, and interstitial space. Several transport mechanisms are involved in the fine-tuning and regulation of extra- and intracellular pH. The sodium-independent electroneutral anion exchangers (AEs) exchange intracellular bicarbonate for extracellular chloride and thereby lower the intracellular pH. Recently, a significant association was found with the variant Ala867Asp of the anion exchanger AE3, which is predominantly expressed in brain and heart, in a large cohort of patients with idiopathic generalized epilepsy. To analyze a possible involvement of AE3 dysfunction in the pathogenesis of seizures, we generated an AE3-knockout mouse model by targeted disruption of Slc4a3. AE3-knockout mice were apparently healthy, and neither displayed gross histological and behavioral abnormalities nor spontaneous seizures or spike wave complexes in electrocorticograms. However, the seizure threshold of AE3-knockout mice exposed to bicuculline, pentylenetetrazole, or pilocarpine was reduced, and seizure-induced mortality was significantly increased compared to wild-type littermates. In the pyramidal cell layer of the hippocampal CA3 region, where AE3 is strongly expressed, disruption of AE3 abolished sodium-independent chloride-bicarbonate exchange. These findings strongly support the hypothesis that AE3 modulates seizure susceptibility and, therefore, are of significance for understanding the role of intracellular pH in epilepsy.
Keywords:Antiporters, Bicuculline, Brain, Chloride-Bicarbonate Antiporters, Convulsants, Dentate Gyrus, Gene Targeting, Hydrogen-Ion Concentration, Pentylenetetrazole, Pilocarpine, Seizures, Sensory Thresholds, Animals, Mice
Source:Molecular and Cellular Biology
Publisher:American Society for Microbiology
Page Range:182-191
Date:January 2006
Official Publication:https://doi.org/10.1128/MCB.26.1.182-191.2006
PubMed:View item in PubMed

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