title: Na+ channel expression and neuronal function in the Na+/H+ exchanger 1 null mutant mouse.
abstract: 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.
authors.affiliation: Department of Pediatrics (Section of Respiratory Medicine), Yale University School of Medicine, New Haven, Connecticut 06520, USA. ying.xia@yale.edu
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Jin
authors.initials: J
authors.lastname: Xue
authors.forename: Xiang Q
authors.initials: XQ
authors.lastname: Gu
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Sun
authors.forename: Hang
authors.initials: H
authors.lastname: Yao
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Haddad
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D004827:Epilepsy / Q000209:etiology / Q000503:physiopathology*; D006624:Hippocampus / Q000166:cytology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D019579:Neocortex / Q000166:cytology / Q000503:physiopathology; D009474:Neurons / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: D015222:Sodium Channels; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D012964:Sodium