Mutation I810N in the a3 isoform of Na super(+),K super(+)-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-01, Vol.106 (33), p.14085-14090
• Main Authors: Clapcote, Steven J, Duffy, Steven, Xie, Gang, Kirshenbaum, Greer, Bechard, Allison R, Rodacker Schack, Vivien, Petersen, Janne, Sinai, Laleh, Saab, Bechara J, Lerch, Jason P, Minassian, Berge A, Ackerley, Cameron A, Sled, John G, Cortez, Miguel A, Henderson, Jeffrey T, Vilsen, Bente, Roder, John C
• Format: Article
• Language: English
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0904817106

In a mouse mutagenesis screen, we isolated a mutant, Myshkin (Myk), with autosomal dominant complex partial and secondarily generalized seizures, a greatly reduced threshold for hippocampal seizures in vitro, posttetanic hyperexcitability of the CA3-CA1 hippocampal pathway, and neuronal degeneration in the hippocampus. Positional cloning and functional analysis revealed that Myk/+ mice carry a mutation (I810N) which renders the normally expressed Na super(+),K super(+)-ATPase a3 isoform inactive. Total Na super(+),K super(+)-ATPase activity was reduced by 42% in Myk/+ brain. The epilepsy in Myk/+ mice and in vitro hyperexcitability could be prevented by delivery of additional copies of wild-type Na super(+),K super(+)-ATPase a3 by transgenesis, which also rescued Na super(+),K super(+)-ATPase activity. Our findings reveal the functional significance of the Na super(+),K super(+)-ATPase a3 isoform in the control of epileptiform activity and seizure behavior.