Myelin Loss and Axonal Ion Channel Adaptations Associated with Gray Matter Neuronal Hyperexcitability
Myelin Loss and Axonal Ion Channel Adaptations Associated with Gray Matter Neuronal Hyperexcitability
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DOI：
10.1523/jneurosci.4747-14.2015
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发表时间：
2015-05-06
影响因子：
5.3
通讯作者：
Kole, Maarten H. P.
中科院分区：
文献类型：
--
作者：
Hamada, Mustafa S.;Kole, Maarten H. P.
髓鞘形成和电压门控离子通道聚集在节点的Ranvier是必不可少的快速跳跃传导的动作电位。髓鞘形成是否影响轴突起始段（AIS）和动作电位起始的结构组织知之甚少。使用cuprizone小鼠模型，我们结合电生理记录与电压门控Nav1.6和Kv7.3亚基和锚定蛋白的免疫荧光分析单个脱髓鞘的新皮层L5轴突的功能和结构特性。全细胞记录表明，脱髓鞘轴突的神经元本质上更兴奋，其特征在于增加自发阈上去极化以及逆向传播的动作电位异位产生的轴突的远端部分。脱髓鞘轴突的免疫荧光检查表明，β IV-血影蛋白，Nav1.6，和Kv7.3通道在节点的Ranvier要么溶解或延伸到结旁域。与此相反，虽然AIS在脱髓鞘轴突开始更接近索马，锚蛋白G，β IV-血影蛋白，和离子通道的表达保持。受AIS位置和现实树突和轴突形态的限制，结构-功能分析和计算建模证实，AIS的更近端发作略微降低了动作电位产生的功效，表明了补偿作用。这些结果表明，少突胶质细胞髓鞘形成不仅是重要的最大化传导速度，但也限制过度兴奋的锥体神经元。
Myelination and voltage-gated ion channel clustering at the nodes of Ranvier are essential for the rapid saltatory conduction of action potentials. Whether myelination influences the structural organization of the axon initial segment (AIS) and action potential initiation is poorly understood. Using the cuprizone mouse model, we combined electrophysiological recordings with immunofluorescence of the voltage-gated Nav1.6 and Kv7.3 subunits and anchoring proteins to analyze the functional and structural properties of single demyelinated neocortical L5 axons. Whole-cell recordings demonstrated that neurons with demyelinated axons were intrinsically more excitable, characterized by increased spontaneous suprathreshold depolarizations as well as antidromically propagating action potentials ectopically generated in distal parts of the axon. Immunofluorescence examination of demyelinated axons showed that beta IV-spectrin, Nav1.6, and the Kv7.3 channels in nodes of Ranvier either dissolved or extended into the paranodal domains. In contrast, while the AIS in demyelinated axons started more closely to the soma, ankyrin G, beta IV-spectrin, and the ion channel expression were maintained. Structure-function analysis and computational modeling, constrained by the AIS location and realistic dendritic and axonal morphologies, confirmed that a more proximal onset of the AIS slightly reduced the efficacy of action potential generation, suggesting a compensatory role. These results suggest that oligodendroglial myelination is not only important for maximizing conduction velocity, but also for limiting hyperexcitability of pyramidal neurons.