J Neurophysiol (January 1, 2003). 10.1152/jn.00488.2002
Submitted on Submitted 20 June 2002; accepted in final form 10 October 2002

Na⁺ Channel Expression and Neuronal Function in the Na⁺/H⁺ Exchanger 1 Null Mutant Mouse

Departments of  ¹Pediatrics (Section of Respiratory Medicine) and  ²Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520

Xia, Ying, Peng Zhao, Jin Xue, Xiang Q. Gu, Xiaolu Sun, Hang Yao, and Gabriel G. Haddad. Na⁺ Channel Expression and Neuronal Function in the Na⁺/H⁺ Exchanger 1 Null Mutant Mouse. J. Neurophysiol. 89: 229-236, 2003. 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.