Open AccessMice with a Targeted Disruption of the Cl−/HCO3− Exchanger AE3 Display a Reduced Seizure Threshold
Author(s) -
Moritz Hentschke,
Martin Wiemann,
Suna Hentschke,
Ingo Kurth,
Irm HermansBorgmeyer,
Thomas Seidenbecher,
Thomas J. Jentsch,
Andreas Gal,
Christian A. Hübner
Publication year - 2006
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.26.1.182-191.2006
Subject(s) - intracellular ph , intracellular , extracellular , epilepsy , pilocarpine , hippocampal formation , biology , endocrinology , knockout mouse , medicine , sodium , microbiology and biotechnology , chemistry , neuroscience , biochemistry , receptor , organic chemistry
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 ofSlc4a3 . 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.