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

M Hentschke, M Wiemann, S Hentschke… - … and Cellular Biology, 2006 - Taylor & Francis
M Hentschke, M Wiemann, S Hentschke, I Kurth, I Hermans-Borgmeyer, T Seidenbecher…
Molecular and Cellular Biology, 2006Taylor & Francis
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 …
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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