Increased neuronal excitability and seizures in the Na(+)/H(+) exchanger null mutant mouse.
Mice lacking the Na(+)/H(+) exchanger isoform 1 (NHE1) manifest neurological diseases that include ataxia, motor deficits, and a seizure disorder. The molecular basis for the phenotype has not been clear, and it has not been determined how the lack of NHE1 leads, in particular, to the seizure disorder. We have shown in this work that hippocampal CA1 neurons in mutant mice have a much higher excitability than in wild-type mice. This higher excitability is partly based on an upregulation of the Na(+) current density (608.2 +/- 123.2 pA/pF in NHE1 mutant vs. 334.7 +/- 63.7 pA/pF in wild type in HCO/CO(2)). Alterations in Na(+) channel characteristics, including steady-state inactivation (shift of 18 mV in the depolarization direction in the mutant), recovery from inactivation (tau(h) = 5.22 +/- 0.49 ms in wild-type neurons and 2.20 +/- 0.20 ms in mutant neurons), and deactivation (at -100 mV, tau(d) = 1.75 +/- 0.53 ms in mutant and 0.21 +/- 0.05 ms in wild-type neurons) further enhance the differences in excitability between mutant and wild-type mice. Our investigation demonstrates the existence of an important functional interaction between the NHE1 protein and the voltage-sensitive Na(+) channel. We hypothesize that the increased neuronal excitability and possibly the seizure disorder in mice lacking the NHE1 is due, at least in part, to changes in Na(+) channel expression and/or regulation.
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Department of Pediatrics, Section of Respiratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Yao
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Haddad
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D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001639:Bicarbonates / Q000494:pharmacology; D002245:Carbon Dioxide / Q000494:pharmacology; D004553:Electric Conductivity; D006531:HEPES / Q000494:pharmacology; D006706:Homeostasis; D051379:Mice; D008817:Mice, Mutant Strains / Q000235:genetics; D009154:Mutation / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D012640:Seizures / Q000235:genetics / Q000503:physiopathology*; D015222:Sodium Channels / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics*
D001639:Bicarbonates; D015222:Sodium Channels; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D002245:Carbon Dioxide; D006531:HEPES