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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(+),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.

Original publication

DOI

10.1073/pnas.0904817106

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

18/08/2009

Volume

106

Pages

14085 - 14090

Keywords

Animals, Base Sequence, COS Cells, Central Nervous System, Chlorocebus aethiops, Hippocampus, Male, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Mutation, Seizures, Sequence Homology, Nucleic Acid, Sodium-Potassium-Exchanging ATPase