Department of Neurobiology, Capital Medical University, Beijing 100069, China; Key Laboratory for the Neurodegenerative Disorders of the Chinese Ministry of Education, Beijing 100069, China; Beijing Institute for Brain Disorders, Beijing 100069, China.
Department of Physiology, Capital Medical University, Beijing 100069, China; Key Laboratory for the Neurodegenerative Disorders of the Chinese Ministry of Education, Beijing 100069, China; Beijing Institute for Brain Disorders, Beijing 100069, China.
Exp Neurol. 2018 Feb;300:135-148. doi: 10.1016/j.expneurol.2017.11.006. Epub 2017 Nov 8.
The glutamatergic projection from the motor cortex to the subthalamic nucleus (STN) constitutes the cortico-basal ganglia circuit and plays a critical role in the control of movement. Emerging evidence shows that the cortico-STN pathway is susceptible to dopamine depletion. Specifically in Parkinson's disease (PD), abnormal electrophysiological activities were observed in the motor cortex and STN, while the STN serves as a key target of deep brain stimulation for PD therapy. However, direct morphological changes in the cortico-STN connectivity in response to PD progress are poorly understood at present. In the present study, we used a trans-synaptic anterograde tracing method with herpes simplex virus-green fluorescent protein (HSV-GFP) to monitor the cortico-STN connectivity in a rat model of PD. We found that the connectivity from the primary motor cortex (M1) to the STN was impaired in parkinsonian rats as manifested by a marked decrease in trans-synaptic infection of HSV-GFP from M1 neurons to STN neurons in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. Ultrastructural analysis with electron microscopy revealed that excitatory synapses in the STN were also impaired in parkinsonian rats. Glutamatergic terminals identified by a specific marker (vesicular glutamate transporter 1) were reduced in the STN, while glutamatergic neurons showed an insignificant change in their total number in both the M1 and STN regions. These results indicate that the M1-STN glutamatergic connectivity is downregulated in parkinsonian rats. This downregulation is mediated probably via a mechanism involving the impairments of excitatory terminals and synapses in the STN.
来自运动皮层到丘脑底核（STN）的谷氨酸能投射构成了皮质基底节回路，并在运动控制中发挥着关键作用。新出现的证据表明，皮质-STN 通路易受多巴胺耗竭的影响。具体在帕金森病（PD）中，观察到运动皮层和 STN 中出现异常的电生理活动，而 STN 是 PD 深部脑刺激治疗的关键靶点。然而，目前对于 PD 进展中皮质-STN 连接的直接形态变化知之甚少。在本研究中，我们使用单纯疱疹病毒-绿色荧光蛋白（HSV-GFP）的顺行转导示踪方法来监测 PD 大鼠模型中的皮质-STN 连接。我们发现，帕金森病大鼠的皮质-STN 连接受损，表现为单侧 6-羟多巴胺（6-OHDA）损伤大鼠中 M1 神经元到 STN 神经元的 HSV-GFP 顺行感染显著减少。电镜下的超微结构分析显示，帕金森病大鼠的 STN 中的兴奋性突触也受损。STN 中的谷氨酸能末梢（通过特定标志物囊泡谷氨酸转运体 1 识别）减少，而谷氨酸能神经元在 M1 和 STN 区域的总数没有明显变化。这些结果表明，帕金森病大鼠的 M1-STN 谷氨酸能连接被下调。这种下调可能是通过 STN 中兴奋性末梢和突触的损伤机制介导的。
