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1 Department of Pediatrics (Section of Respiratory Medicine), Yale University School of Medicine, New Haven, CT, USA
2 Department of Pediatrics (Section of Respiratory Medicine), Yale University School of Medicine, New Haven, CT, USA; Department of Cellular and Molecular Physiology, Yale university School of Medicine, New Haven, CT, USA
* To whom correspondence should be addressed. E-mail: ying.xia{at}yale.edu.
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: i) is the increased excitability limited to CA1 neurons? ii) is the increased Na+ current density related to an increased Na+ channel expression? and 3) If so, which Na+ channel is up-regulated? Using neurophysiological, autoradiographic and immunoblotting techniques, we showed that 1) both CA1 and cortical neurons have an increased membrane excitability; 2) Na+ channel density is selectively up-regulated in the hippocampus and cortex (P,0.05); and 3) Na+ channel subtype I is increased in the hippocampus and Na+ channel subtype II is increased in the cortex. Our results demonstrate that mice lacking NHE1 up-regulate 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 over-excitability due to Na+ channel up-regulation in the hippocampus and cortex forms the basis of epileptic seizures in NHE1 mutant mice.
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