Neychev Vladimir K, Fan Xueliang, Mitev V I, Hess Ellen J, Jinnah H A
Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
Brain. 2008 Sep;131(Pt 9):2499-509. doi: 10.1093/brain/awn168. Epub 2008 Jul 26.
Dystonia is a neurological disorder characterized by excessive involuntary muscle contractions that lead to twisting movements or abnormal posturing. Traditional views place responsibility for dystonia with dysfunction of basal ganglia circuits, yet recent evidence has pointed towards cerebellar circuits as well. In the current studies we used two strategies to explore the hypothesis that the expression of dystonic movements depends on influences from a motor network that includes both the basal ganglia and cerebellum. The first strategy was to evaluate the consequences of subthreshold lesions of the striatum in two different animal models where dystonic movements are thought to originate from abnormal cerebellar function. The second strategy employed microdialysis to search for changes in striatal dopamine release in these two animal models where the cerebellum has been already implicated. One of the animal models involved tottering mice, which exhibit paroxysmal dystonia due to an inherited defect affecting calcium channels. In keeping with prior results implicating the cerebellum in this model, surgical removal of the cerebellum eliminated their dystonic attacks. In contrast, subclinical lesions of the striatum with either 6-hydroxydopamine (6OHDA) or quinolinic acid (QA) exaggerated their dystonic attacks. Microdialysis of the striatum revealed dystonic attacks in tottering mice to be associated with a significant reduction in extracellular striatal dopamine. The other animal model involved the induction of dystonia via pharmacological excitation of the cerebellar cortex by local application of kainic acid in normal mice. In this model the site of stimulation determines the origin of dystonia in the cerebellum. However, subclinical striatal lesions with either 6OHDA or QA again exaggerated their generalized dystonia. When dystonic movements were triggered by pharmacological stimulation of the cerebellum, microdialysis revealed significant reductions in striatal dopamine release. These results demonstrate important functional relationships between cerebellar and basal ganglia circuits in two different animal models of dystonia. They suggest that expression of dystonic movements depends on influences from both basal ganglia and cerebellum in both models. These results support the hypothesis that dystonia may result from disruption of a motor network involving both the basal ganglia and cerebellum, rather than isolated dysfunction of only one motor system.
肌张力障碍是一种神经疾病，其特征为过度的不自主肌肉收缩，导致扭曲动作或异常姿势。传统观点认为肌张力障碍是由基底神经节回路功能障碍引起的，但最近的证据也指向了小脑回路。在当前的研究中，我们使用了两种策略来探究肌张力障碍性运动的表达是否依赖于一个包括基底神经节和小脑的运动网络的影响这一假设。第一种策略是在两种不同的动物模型中评估纹状体阈下损伤的后果，在这些模型中，肌张力障碍性运动被认为源于异常的小脑功能。第二种策略是使用微透析来寻找这两种已涉及小脑的动物模型中纹状体多巴胺释放的变化。其中一种动物模型是蹒跚小鼠，由于影响钙通道的遗传缺陷，它们会出现阵发性肌张力障碍。与之前表明小脑参与该模型的结果一致，手术切除小脑消除了它们的肌张力障碍发作。相比之下，用6-羟基多巴胺（6OHDA）或喹啉酸（QA）对纹状体进行亚临床损伤会加剧它们的肌张力障碍发作。对纹状体进行微透析发现，蹒跚小鼠的肌张力障碍发作与细胞外纹状体多巴胺的显著减少有关。另一种动物模型是通过在正常小鼠局部应用 kainic 酸对小脑皮质进行药理学刺激来诱导肌张力障碍。在这个模型中，刺激部位决定了小脑肌张力障碍的起源。然而，用6OHDA或QA对纹状体进行亚临床损伤再次加剧了它们的全身性肌张力障碍。当通过对小脑的药理学刺激引发肌张力障碍性运动时，微透析显示纹状体多巴胺释放显著减少。这些结果证明了在两种不同的肌张力障碍动物模型中小脑和基底神经节回路之间重要的功能关系。它们表明在这两种模型中，肌张力障碍性运动的表达依赖于基底神经节和小脑的影响。这些结果支持了这样一种假设，即肌张力障碍可能是由涉及基底神经节和小脑的运动网络的破坏引起的，而不是仅由一个运动系统的孤立功能障碍引起的。
