Increased neuronal excitability and seizures in the Na+/H+ exchanger null mutant mouse

Mice lacking the Na+/H+ exchanger isoform 1 (NHE1) manifest neurological di seases that include ataxia, motor deficits, and a seizure disorder. The mol ecular basis for the phenotype has not been clear, and it has not been dete rmined 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 excitabilit y 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 HCO3-/C O2). Alterations in Na+ channel characteristics, including steady-state ina ctivation (shift of 18 mV in the depolarization direction in the mutant), r ecovery 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-ty pe mice. Our investigation demonstrates the existence of an important funct ional interaction between the NHE1 protein and the voltage-sensitive Na+ ch annel. 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.