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

Abstract

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

Mania-like behavior induced by genetic dysfunction of the neuron-specific Na + ,K + -ATPase α3 sodium pump

“…In contrast to N12 C57BL/6NCr Myk/ + mice, Myk/ + mice at N20 C57BL/6NCr did not show stress-induced seizure activity in ECoG recordings and had increased total brain NKA activity. These results support our previous finding that an increase in NKA activity contributes to seizure resistance (21). Nonetheless, the possibility remains that unobserved subcortical epileptiform discharges contribute to mania-like behavior in Myk/ + mice.…”

“…Briefly, the Myk/ + mutation was created through N-nitroso-Nethylurea mutagenesis and results in a normally expressed but inactive enzyme, leading to a 36% to 42% reduction in total NKA activity in the brain (21). Mutations in the ATP1A3 gene have been identified in rapid-onset dystonia parkinsonism; however, a known rapid-onset dystonia parkinsonism mutation reduces Na + binding, whereas the Myk/ + mutation is inactivating (22).…”

“…Previously, we reported that Myk/ + mice backcrossed 12 generations (N12) to the C57BL/ 6NCr strain display increased susceptibility to stress-induced seizures (21). In the current study, we used Myk/ + mice that were backcrossed to the seizure-resistant C57BL/6NCr strain (23) for 20 generations (N20).…”

α3Na+/K+-ATPase Deficiency Causes Brain Ventricle Dilation and Abrupt Embryonic Motility in Zebrafish

“…Currently, two different genetically modified mouse models targeting the Atp1a3 gene exist: ␣ 3 ϩ/Ϫ KI I4 (14) and ␣ 3 ϩ/Ϫ -KI I810N (Myshkin) (15). These mice display learning/memory deficits (14), epilepsy/seizures (15), stress-induced motor symptoms (16), anxious phenotype, and depression-like behavior (17).…”

“…These mice display learning/memory deficits (14), epilepsy/seizures (15), stress-induced motor symptoms (16), anxious phenotype, and depression-like behavior (17). However, they do not fully capture the human RDP symptoms, and the pathology of RDP remains unsolved.…”