Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 33, Pages 14085-14090Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0904817106
Keywords
alpha3 Na+,K+ ATPase; BAC rescue; epilepsy; forward genetic screen; mouse
Categories
Funding
- Canadian Institutes of Health Research [MOP 94856]
- Lundbeck Foundation
- Novo Nordisk Foundation
- Danish Medical Research Council
- Danish National Research Foundation
- Royal Society of London
- National Alliance for Research on Schizophrenia and Depression
- Canadian Institutes of Health
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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 alpha 3 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 alpha 3 by transgenesis, which also rescued Na+,K+-ATPase activity. Our findings reveal the functional significance of the Na+,K+-ATPase alpha 3 isoform in the control of epileptiform activity and seizure behavior.
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