• Steven J Clapcote, Steven Duffy, Gang Xie, Greer Kirshenbaum, Allison R Bechard, Vivien Rodacker Schack, Janne Petersen, Laleh Sinai, Bechara J Saab, Jason P Lerch, Berge A Minassian, Cameron A Ackerley, John G Sled, Miguel A Cortez, Jeffrey T Henderson, Bente Vilsen, and John C Roder.
• Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5. s.j.clapcote@leeds.ac.uk
• Proc. Natl. Acad. Sci. U.S.A. 2009 Aug 18;106(33):14085-90.

AbstractIn 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(+),K(+)-ATPase alpha3 isoform inactive. Total Na(+),K(+)-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(+),K(+)-ATPase alpha3 by transgenesis, which also rescued Na(+),K(+)-ATPase activity. Our findings reveal the functional significance of the Na(+),K(+)-ATPase alpha3 isoform in the control of epileptiform activity and seizure behavior.

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