Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage
Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage
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DOI：
10.1093/brain/awl024
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发表时间：
2006-04-01
期刊：
影响因子：
14.5
通讯作者：
Bostock, H
中科院分区：
文献类型：
--
作者：
Kanai, K;Kuwabara, S;Bostock, H
肌萎缩侧索硬化症（ALS）的一个特征性特征是束状结构，可以发生在运动神经元的近端或远端，表明膜兴奋性受到广泛的干扰。先前对轴突兴奋性特性（即阈值电张力，强度-持续时间常数）的研究分别表明，钾通道或钠通道的变化可能参与其中。为了重新研究这些变化并探讨它们与疾病分期的相关性，我们测量了58例ALS患者腕部正中神经的多轴突兴奋性特性（阈值电张力、强度-持续时间常数、恢复周期和电流-阈值关系），并与25例年龄匹配的对照组进行了比较。ALS患者去极化阈值电张力变化更大（即调节更少）（P < 0.001），恢复周期异常更大（P < 0.001）。这些异常在CMAP中度降低（1-5 mV）的患者中更为突出。对这一组的兴奋性变化进行建模，支持轴突钾电导降低的假设，尽管膜去极化，但仍导致异常性增加。肌萎缩侧索硬化症中强度-持续时间常数的延长趋势仅在CMAP幅值正常（> - 5 mV）的患者中有统计学意义。仅CMAP严重降低（< 1 mV）的患者对超极化电流的阈值变化降低。这些结果提示异常膜性质随疾病进展而改变。首先，持续的Na+电导增加，可能与侧枝发芽有关，然后K+电导下降。这两种变化都会引起轴突的高兴奋性，并可能导致束控的产生。轴突特性的这些系列变化可以为ALS的病理生理学提供见解，并对未来的治疗选择产生影响。
Fasciculations are a characteristic feature of amyotrophic lateral sclerosis (ALS), and can arise proximally or distally in the motor neuron, indicating a widespread disturbance in membrane excitability. Previous studies of axonal excitability properties (i.e. threshold electrotonus, strength-duration time constant) have suggested respectively that change in potassium or sodium channels may be involved. To reinvestigate these changes and explore their correlation with disease stage, multiple axonal excitability properties (threshold electrotonus, strength-duration time constant, recovery cycle and current-threshold relationship) were measured for the median nerve at the wrist in 58 ALS patients, and compared with 25 age-matched controls. In ALS, there were greater changes in depolarizing threshold electrotonus (i.e. less accommodation) (P < 0.001) and greater supernormality in the recovery cycles (P < 0.001). These abnormalities were more prominent in patients with moderately reduced CMAP (1-5 mV). Modelling the excitability changes in this group supported the hypothesis that axonal potassium conductances are reduced, resulting in increased supernormality despite membrane depolarization. The tendency for strength-duration time constant to be prolonged in ALS was only significant for patients with normal CMAP amplitude (> 5 mV). Patients with severely reduced CMAP (< 1 mV) alone showed reduced threshold changes to hyperpolarizing current. These results suggest a changing pattern of abnormal membrane properties with disease progression. First, persistent Na+ conductance increases, possibly associated with collateral sprouting, and then K+ conductances decline. Both changes cause axonal hyperexcitability, and may contribute to the generation of fasciculations. These serial changes in axonal properties could provide insights into the pathophysiology of ALS, and implications for future therapeutic options.