Clapcote Steven J, Duffy Steven, Xie Gang, Kirshenbaum Greer, Bechard Allison R, Rodacker Schack Vivien, Petersen Janne, Sinai Laleh, Saab Bechara J, Lerch Jason P, Minassian Berge A, Ackerley Cameron A, Sled John G, Cortez Miguel A, Henderson Jeffrey T, Vilsen Bente, Roder John C
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5.
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14085-90. doi: 10.1073/pnas.0904817106. Epub 2009 Aug 3.
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.
在一项小鼠诱变筛选中，我们分离出了一个名为Myshkin（Myk）的突变体，其具有常染色体显性遗传性复杂部分性发作继而全身性发作，体外海马体发作阈值大幅降低，海马体CA3-CA1通路强直后超兴奋性，以及海马体神经元变性。定位克隆和功能分析表明，Myk/+小鼠携带一个突变（I810N），该突变使正常表达的Na(+)，K(+)-ATP酶α3亚型失活。Myk/+小鼠大脑中的总Na(+)，K(+)-ATP酶活性降低了42%。通过转基因导入额外的野生型Na(+)，K(+)-ATP酶α3拷贝，可以预防Myk/+小鼠的癫痫发作和体外超兴奋性，这也挽救了Na(+)，K(+)-ATP酶活性。我们的研究结果揭示了Na(+)，K(+)-ATP酶α3亚型在控制癫痫样活动和发作行为中的功能意义。
