小胶质细胞可能通过选择性吞噬丘脑底核谷氨酸能突触来代偿多巴胺能神经元丢失造成的帕金森模型鼠的功能缺失

Microglia may compensate for dopaminergic neuron loss in experimental Parkinsonism through selective elimination of glutamatergic synapses from the subthalamic nucleus

当帕金森患者出现临床症状时,其黑质致密部的绝大部分多巴胺神经元已发生退行性改变。这提示可能存在某些代偿机制,延缓了临床症状的出现。本研究制作6-羟多巴胺诱导的偏侧帕金森大鼠模型,观察位于黑质下网状部和苍白球的激活的小胶质细胞在代偿机制中的作用。研究发现,在偏侧帕金森大鼠中,黑质下网状部聚集的激活的小胶质细胞远多于苍白球中。激活的小胶质细胞胞体增大并表达吞噬物标志物CD68和NG2蛋白多糖。激活的小胶质细胞聚集在黑质下网状部的特定部位,该部位的突触蛋白I和突触后密集蛋白95的表达降低。活化的小胶质细胞吞噬突触前、后膜上的各种蛋白,包括NMDA受体。将红色荧光标记物Di I作为顺行示踪剂注入丘脑底核,可见黑质下网状部和苍白球内的细胞吞噬了Di I。在谷氨酸刺激下,原代培养的小胶质细胞吞噬活动增强,编码吞噬相关因子的m RNA转录水平也增加。人工合成的糖皮质激素地塞米松可以减弱这种改变。给PD大鼠皮下注射地塞米松,可以抑制黑质下网状部小胶质细胞的活化,运动功能障碍进一步加重,谷氨酸能突触转录m RNA增加,GABA能突触转录m RNA水平未增加。这些发现提示,当谷氨酸能神经元活动增强时,黑质下网状部和苍白球的小胶质细胞活化,选择性吞噬丘脑底核的谷氨酸能突触。因此,在基底核区可能存在一个负反馈环路,间接地代偿了由于多巴胺能神经元丢失而导致的功能障碍。小胶质细胞在这个负反馈环路中扮演了重要的角色。

Abstract 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.