Meissner Wassilios, Guigoni Celine, Cirilli Laetitia, Garret Maurice, Bioulac Bernard H, Gross Christian E, Bezard Erwan, Benazzouz Abdelhamid
CNRS UMR 5227, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France.
Eur J Neurosci. 2007 Mar;25(5):1492-500. doi: 10.1111/j.1460-9568.2007.05406.x.
The mechanisms of action of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) remain only partially understood. Hitherto, experimental studies have suggested that STN-HFS reduces the activity of STN neurons. However, some recent reports have challenged this view, showing that STN-HFS might also increase the activity of globus pallidus internalis (GPi) neurons that are under strong excitatory drive of the STN. In addition, most results emanate from studies applying acute STN-HFS, while parkinsonian patients receive chronic stimulation. Thus, the present study was designed to assess the effect of chronic (10 days) STN-HFS in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primate. For this purpose, 2-deoxyglucose (2-DG) uptake, a measure of global synaptic activity, was assessed in the basal ganglia and the motor thalamus after chronic unilateral STN-HFS. Cytochrome oxidase subunit 1 (COI) mRNA expression, a marker of efferent metabolic activity, was additionally assessed in the globus pallidus. Chronic STN-HFS (i) reversed abnormally decreased 2-DG uptake in the STN of parkinsonian nonhuman primates, (ii) reversed abnormally increased 2-DG accumulation in the GPi while COI mRNA expression was increased, suggesting global activation of GPi neurons, and (iii) reversed abnormally increased 2-DG uptake in the ventrolateral motor thalamus nucleus. The simultaneous decrease in 2-DG uptake and increase in COI mRNA expression are difficult to reconcile with the current model of basal ganglia function and suggest that the mechanisms by which STN-HFS exerts its clinical benefits are more complex than a simple reversal of abnormal activity in the STN and its targets.
丘脑底核（STN）高频刺激（HFS）的作用机制仍仅被部分理解。迄今为止，实验研究表明STN-HFS可降低STN神经元的活性。然而，最近一些报告对这一观点提出了质疑，表明STN-HFS也可能增加受STN强烈兴奋性驱动的苍白球内侧部（GPi）神经元的活性。此外，大多数结果来自应用急性STN-HFS的研究，而帕金森病患者接受的是慢性刺激。因此，本研究旨在评估慢性（10天）STN-HFS对1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理的非人类灵长类动物的影响。为此，在慢性单侧STN-HFS后，评估了基底神经节和运动丘脑的2-脱氧葡萄糖（2-DG）摄取，这是一种整体突触活性的测量指标。还在苍白球中评估了细胞色素氧化酶亚基1（COI）mRNA表达，这是传出代谢活性的标志物。慢性STN-HFS（i）逆转了帕金森病非人类灵长类动物STN中异常降低的2-DG摄取，（ii）逆转了GPi中异常增加的2-DG积累，同时COI mRNA表达增加，表明GPi神经元整体激活，以及（iii）逆转了腹外侧运动丘脑核中异常增加的2-DG摄取。2-DG摄取的同时减少和COI mRNA表达的增加难以与当前的基底神经节功能模型相协调，这表明STN-HFS发挥其临床益处的机制比简单地逆转STN及其靶点的异常活动更为复杂。
