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 ␣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 ␣3 by transgenesis, which also rescued Na ؉ ,K ؉ -ATPase activity. Our findings reveal the functional significance of the Na ؉ ,K ؉ -ATPase ␣3 isoform in the control of epileptiform activity and seizure behavior.alpha3 Na ϩ ,K ϩ ATPase ͉ BAC rescue ͉ epilepsy ͉ forward genetic screen ͉ mouse

Endogenous period is extended in Myk/ + due to longer periods of (I) activity (α). All data are presented as means ± SEM, *P < 0.05, **P < 0.01; ***P < 0.001 compared with +/+ mice.