Mutation I810N in the α3 isoform of Na+,K+-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

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 α3 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 α3 by transgenesis, which also rescued Na⁺,K⁺-ATPase activity. Our findings reveal the functional significance of the Na⁺,K⁺-ATPase α3 isoform in the control of epileptiform activity and seizure behavior.