Mice with a targeted disruption of the Cl-/HCO3- exchanger AE3 display a reduced seizure threshold.
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Mice with a targeted disruption of the Cl-/HCO3- exchanger AE3 display a reduced seizure threshold. / Hentschke, Moritz; Wiemann, Martin; Hentschke, Suna; Kurth, Ingo; Hermans-Borgmeyer, Irm; Seidenbecher, Thomas; Jentsch, Thomas J; Gal, Andreas; Hübner, Christian.
in: MOL CELL BIOL, Jahrgang 26, Nr. 1, 1, 2006, S. 182-191.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Mice with a targeted disruption of the Cl-/HCO3- exchanger AE3 display a reduced seizure threshold.
AU - Hentschke, Moritz
AU - Wiemann, Martin
AU - Hentschke, Suna
AU - Kurth, Ingo
AU - Hermans-Borgmeyer, Irm
AU - Seidenbecher, Thomas
AU - Jentsch, Thomas J
AU - Gal, Andreas
AU - Hübner, Christian
PY - 2006
Y1 - 2006
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 26
SP - 182
EP - 191
JO - MOL CELL BIOL
JF - MOL CELL BIOL
SN - 0270-7306
IS - 1
M1 - 1
ER -
