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Dendritic Kv3.3 Potassium Channels in Cerebellar Purkinje Cells Regulate Generation and Spatial Dynamics of Dendritic Ca2+ Spikes

机译:小脑浦肯野细胞中的树突状Kv3.3钾通道调节树突状Ca2 +突触的生成和空间动力学。

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摘要

Purkinje cell dendrites are excitable structures with intrinsic and synaptic conductances contributing to the generation and propagation of electrical activity. Voltage-gated potassium channel subunit Kv3.3 is expressed in the distal dendrites of Purkinje cells. However, the functional relevance of this dendritic distribution is not understood. Moreover, mutations in Kv3.3 cause movement disorders in mice and cerebellar atrophy and ataxia in humans, emphasizing the importance of understanding the role of these channels. In this study, we explore functional implications of this dendritic channel expression and compare Purkinje cell dendritic excitability in wild-type and Kv3.3 knockout mice. We demonstrate enhanced excitability of Purkinje cell dendrites in Kv3.3 knockout mice, despite normal resting membrane properties. Combined data from local application pharmacology, voltage clamp analysis of ionic currents, and assessment of dendritic Ca2+ spike threshold in Purkinje cells suggest a role for Kv3.3 channels in opposing Ca2+ spike initiation. To study the physiological relevance of altered dendritic excitability, we measured [Ca2+]i changes throughout the dendritic tree in response to climbing fiber activation. Ca2+ signals were specifically enhanced in distal dendrites of Kv3.3 knockout Purkinje cells, suggesting a role for dendritic Kv3.3 channels in regulating propagation of electrical activity and Ca2+ influx in distal dendrites. These findings characterize unique roles of Kv3.3 channels in dendrites, with implications for synaptic integration, plasticity, and human disease.
机译:浦肯野细胞树突是具有固有和突触电导的兴奋性结构,有助于电活动的产生和传播。电压门控钾通道亚基Kv3.3在浦肯野细胞的远端树突中表达。但是,这种树突分布的功能相关性尚不明确。此外,Kv3.3的突变会引起小鼠运动异常,并导致人类小脑萎缩和共济失调,从而强调了理解这些通道的作用的重要性。在这项研究中,我们探索了这种树突状通道表达的功能含义,并比较了野生型和Kv3.3基因敲除小鼠的Purkinje细胞树突状兴奋性。我们展示了增强的浦肯野细胞树突在Kv3.3基因敲除小鼠中的兴奋性,尽管具有正常的静息膜特性。来自本地应用药理学,离子电流的电压钳分析以及Purkinje细胞中树突状Ca2 +尖峰阈值的评估的综合数据表明,Kv3.3通道在相反的Ca2 +尖峰引发中发挥了作用。为了研究改变的树突状兴奋性的生理相关性,我们测量了整个树状树中[Ca2 +] i对攀岩纤维活化的响应。 Ca2 +信号在Kv3.3基因敲除的Purkinje细胞的远端树突中被特别增强,表明树突状Kv3.3通道在调节远端树突中的电活动和Ca2 +流入的传播中发挥作用。这些发现表征了Kv3.3通道在树突中的独特作用,并暗示了突触整合,可塑性和人类疾病。

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