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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

Moritz Hentschke,1 Martin Wiemann,2 Suna Hentschke,1 Ingo Kurth,1 Irm Hermans-Borgmeyer,3 Thomas Seidenbecher,4 Thomas J. Jentsch,3 Andreas Gal,1 and Christian A. Hübner1*

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.

* Corresponding author. Mailing address: Department of Human Genetics, UKE-Hamburg, Butenfeld 42, 22529 Hamburg, Germany. Phone: 49-40-42803-4536. Fax: 49-40-42803-5098. E-mail: c.huebner{at}uke.uni-hamburg.de.

Molecular and Cellular Biology, January 2006, p. 182-191, Vol. 26, No. 1
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.1.182-191.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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