Mice with a targeted disruption of the Cl-/HCO3- exchanger AE3 display a reduced seizure threshold.
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.
Hentschke
Moritz
M
Department of Human Genetics, UKE-Hamburg, Butenfeld 42, 22529 Hamburg, Germany.
Wiemann
Martin
M
Hentschke
Suna
S
Kurth
Ingo
I
Hermans-Borgmeyer
Irm
I
Seidenbecher
Thomas
T
Jentsch
Thomas J
TJ
Gal
Andreas
A
Hübner
Christian A
CA
D000818:Animals; D017920:Antiporters / Q000235:genetics*; D001640:Bicuculline / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000503:physiopathology; D027963:Chloride-Bicarbonate Antiporters / Q000235:genetics*; D003292:Convulsants / Q000494:pharmacology*; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism; D018390:Gene Targeting; D006863:Hydrogen-Ion Concentration; D051379:Mice; D018345:Mice, Knockout; D010433:Pentylenetetrazole / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D012640:Seizures / Q000235:genetics* / Q000503:physiopathology; D012684:Sensory Thresholds
D017920:Antiporters; D027963:Chloride-Bicarbonate Antiporters; D003292:Convulsants; C062002:Slc4a3 protein, mouse; D010862:Pilocarpine; D010433:Pentylenetetrazole; D001640:Bicuculline