Microglia may compensate for dopaminergic neuron loss in experimental Parkinsonism through selective elimination of glutamatergic synapses from the subthalamic nucleus
Microglia may compensate for dopaminergic neuron loss in experimental Parkinsonism through selective elimination of glutamatergic synapses from the subthalamic nucleus
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DOI：
10.1002/glia.23199
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发表时间：
2017-11-01
期刊：
影响因子：
6.2
通讯作者：
Tanaka, Junya
中科院分区：
文献类型：
--
作者：
Aono, Hitomi;Choudhury, Mohammed Emamussalehin;Tanaka, Junya
帕金森病(PD)的症状直到黑质致密部(SNC)中的大多数多巴胺能神经元退化才会变得明显，这表明代偿机制发挥了作用。在此，我们研究了在6-羟基多巴胺诱导的大鼠偏侧帕金森病模型中，激活的小胶质细胞在黑质网状部(SNR)和苍白球(GP)中的代偿性参与。在模型中，激活的小胶质细胞在SNR内的积聚比在SNC内更明显。细胞胞体增大，在SNR的有限区域表达吞噬标记CD68和NG2蛋白多糖，突触蛋白I和突触后密度95免疫反应减弱。激活的小胶质细胞吞噬了突触前和突触后的成分，包括NMDA受体到它们的吞噬小体中。SNR和GP中的细胞吞噬红色荧光DII，注射到丘脑底核(STN)作为顺行示踪剂。大鼠原代小胶质细胞对谷氨酸的反应增强了吞噬活性，编码吞噬相关因子的mRNA表达增加。合成的糖皮质激素地塞米松克服了谷氨酸的刺激作用。帕金森病模型大鼠皮下注射地塞米松可抑制SNR内小胶质细胞的激活，导致运动功能障碍加重，而编码谷氨酸而不是GABA能的基因表达增加。这些发现表明，SNR和GP中的小胶质细胞被激活，并选择性地消除STN中的谷氨酸能突触，以响应谷氨酸能活性的增加。因此，小胶质细胞可能参与了基底节间接通路的负反馈环，以补偿帕金森病脑内多巴胺能神经元的丢失。
Parkinson's disease (PD) symptoms do not become apparent until most dopaminergic neurons in the substantia nigra pars compacta (SNc) degenerate, suggesting that compensatory mechanisms play a role. Here, we investigated the compensatory involvement of activated microglia in the SN pars reticulata (SNr) and the globus pallidus (GP) in a 6-hydroxydopamine-induced rat hemiparkinsonism model. Activated microglia accumulated more markedly in the SNr than in the SNc in the model. The cells had enlarged somata and expressed phagocytic markers CD68 and NG2 proteoglycan in a limited region of the SNr, where synapsin I- and postsynaptic density 95-immunoreactivities were reduced. The activated microglia engulfed pre- and post-synaptic elements, including NMDA receptors into their phagosomes. Cells in the SNr and GP engulfed red fluorescent DiI that was injected into the subthalamic nucleus (STN) as an anterograde tracer. Rat primary microglia increased their phagocytic activities in response to glutamate, with increased expression of mRNA encoding phagocytosis-related factors. The synthetic glucocorticoid dexamethasone overcame the stimulating effect of glutamate. Subcutaneous single administration of dexamethasone to the PD model rats suppressed microglial activation in the SNr, resulting in aggravated motor dysfunctions, while expression of mRNA encoding glutamatergic, but not GABAergic, synaptic elements increased. These findings suggest that microglia in the SNr and GP become activated and selectively eliminate glutamatergic synapses from the STN in response to increased glutamatergic activity. Thus, microglia may be involved in a negative feedback loop in the indirect pathway of the basal ganglia to compensate for the loss of dopaminergic neurons in PD brains.