Mutations in the gene encoding the alpha3 Na+/K+-ATPase isoform (ATP1A3) lead to movement disorders that manifest with dystonia, a common neurological symptom with many different origins, but for which the underlying molecular mechanisms remain poorly understood. We have generated an ATP1A3 mutant mouse that displays motor impairments and a hyperexcitable motor phenotype compatible with dystonia. We show that neurons harboring this mutation are compromised in their ability to extrude raised levels of intracellular sodium, highlighting a profound deficit in neuronal sodium homeostasis. We show that the spinal motor network in ATP1A3 mutant mice has a reduced responsiveness to activity-dependent rises in intracellular sodium and that this is accompanied by loss of the Na+/K+-ATPase-mediated afterhyperpolarization in motor neurons. Taken together, our data support that the alpha3 Na+/K+-ATPase is important for cellular and spinal motor network homeostasis. These insights suggest that it may be useful to consider ways to compensate for this loss of a critical afterhyperpolarization-dependent control of neuronal excitability when developing future therapies for dystonia.

中文翻译：

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ATP1A3 功能障碍在肌张力障碍模型中导致运动过度兴奋和后超极化丧失


编码 α3 Na+/K+-ATP 酶亚型 （ATP1A3） 的基因突变导致运动障碍，表现为肌张力障碍，肌张力障碍是一种常见的神经系统症状，起源多种多样，但其潜在的分子机制仍知之甚少。我们生成了一种 ATP1A3 突变小鼠，它表现出运动障碍和与肌张力障碍相符的过度兴奋运动表型。我们表明，携带这种突变的神经元在挤出细胞内钠水平升高的能力方面受到损害，突出了神经元钠稳态的严重缺陷。我们表明，ATP1A3 突变小鼠中的脊髓运动网络对细胞内钠活动依赖性升高的反应性降低，并且这伴随着运动神经元中 Na + / K + -ATP 酶介导的后超极化的丢失。综上所述，我们的数据支持 α3 Na + / K + -ATPase 对细胞和脊髓运动网络稳态很重要。这些见解表明，在开发未来的肌张力障碍疗法时，考虑如何补偿这种关键的超极化后依赖性神经元兴奋性的控制损失可能是有用的。