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Molecular and Cellular Biology, January 2006, p. 182-191, Vol. 26, No. 1
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.1.182-191.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Mice with a Targeted Disruption of the Cl^–/HCO₃^– Exchanger AE3 Display a Reduced Seizure Threshold

Department of Human Genetics, UKE-Hamburg, Butenfeld 42, 22529 Hamburg, Germany,¹ Department of Physiology, University of Duisburg—Essen, Hufelandstrasse 55, 45122 Essen, Germany,² ZMNH, University of Hamburg, Falkenried 94, 20251 Hamburg, Germany,³ Institute of Physiology I, Westfälische Wilhelms-University Münster, Robert-Koch-Str. 27a, 48149 Münster, Germany⁴

Received 11 July 2005/ Returned for modification 13 August 2005/ Accepted 9 October 2005

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.

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