Na+ channel expression and neuronal function in the Na+/H+ exchanger 1 null mutant mouse

Mice lacking Na+/H+ exchanger 1 (NHE1) suffer from recurrent seizures and die early postnatally. Although the mechanisms for seizures are not well established, our previous electrophysiological work has shown that neuronal excitability and Na+ current density are increased in hippocampal CA1 neurons of these mutant mice. However, it is unknown whether this increased density is related to altered expression or functional regulation of Na+ channels. In this work, we asked three questions: is the increased excitability limited to CA1 neurons, is the increased Na+ current density related to an increased Na+ channel expression, and, if so, which Na+ channel subtype(s) is upregulated? Using neurophysiological, autoradiographic, and immunoblotting techniques, we showed that both CA1 and cortical neurons have an increase in membrane excitability and Na+ current density; Na+ channel density is selectively upregulated in the hippocampus and cortex (P < 0.05); and Na+ channel subtype I is significantly increased in the hippocampus and Na+ channel subtype II is increased in the cortex. Our results demonstrate that mice lacking NHE1 upregulate their Na+ channel expression in the hippocampal and cortical regions selectively; this leads to an increase in Na+ current density and membrane excitability. We speculate that neuronal overexcitability due to Na+ channel upregulation in the hippocampus and cortex forms the basis of epileptic seizures in NHE1 mutant mice.