Genetic Reduction of the α1 Subunit of Na/K-ATPase Corrects Multiple Hippocampal Phenotypes in Angelman Syndrome
Genetic Reduction of the α1 Subunit of Na/K-ATPase Corrects Multiple Hippocampal Phenotypes in Angelman Syndrome
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DOI：
10.1016/j.celrep.2013.07.005
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发表时间：
2013-08-01
期刊：
影响因子：
8.8
通讯作者：
Klann, Eric
中科院分区：
文献类型：
--
作者：
Kaphzan, Hanoch;Buffington, Shelly A.;Klann, Eric
安杰曼综合征(AS)与自闭症、智力残疾、运动异常和癫痫等症状有关。我们最近发现AS模型小鼠海马区Na/K-ATPaseα1亚单位(α1-NAK)的表达增加，这与轴突起始节段(AIS)蛋白的表达增加有关。我们的发育分析表明，α1-Naka表达的增加先于AIS蛋白的表达。因此，我们假设α1-Naka的过度表达导致AIS异常，通过减少其表达，这些和其他表型可以在AS模型小鼠中得到纠正。在此，我们报告了AS模型小鼠α1-Naka水平的遗传正常化纠正了多种海马表型，包括AIS的改变、固有膜特性的异常、突触可塑性受损和记忆缺陷。这些发现有力地表明，α1-Naka的表达增加在AS模型小鼠海马区的广泛异常中起着重要作用。
Angelman syndrome (AS) is associated with symptoms that include autism, intellectual disability, motor abnormalities, and epilepsy. We recently showed that AS model mice have increased expression of the alpha1 subunit of Na/K-ATPase (alpha 1-NaKA) in the hippocampus, which was correlated with increased expression of axon initial segment (AIS) proteins. Our developmental analysis revealed that the increase in alpha 1-NaKA expression preceded that of the AIS proteins. Therefore, we hypothesized that alpha 1-NaKA overexpression drives AIS abnormalities and that by reducing its expression these and other phenotypes could be corrected in AS model mice. Herein, we report that the genetic normalization of alpha 1-NaKA levels in AS model mice corrects multiple hippocampal phenotypes, including alterations in the AIS, aberrant intrinsic membrane properties, impaired synaptic plasticity, and memory deficits. These findings strongly suggest that increased expression of alpha 1-NaKA plays an important role in a broad range of abnormalities in the hippocampus of AS model mice.