Betarbet R, Porter R H, Greenamyre J T
Department of Neurology, Emory University, Atlanta, Georgia 30322, USA.
J Neurochem. 2000 Mar;74(3):1166-74. doi: 10.1046/j.1471-4159.2000.741166.x.
Nigrostriatal dopaminergic denervation is associated with complex changes in the functional and neurochemical anatomy of the basal ganglia. The excitatory neurotransmitter glutamate mediates neural signaling at crucial points of this circuitry, and glutamate receptors are differentially distributed in the basal ganglia. Available evidence suggests that the glutamatergic corticostriatal and subthalamofugal pathways become overactive after nigrostriatal dopamine depletion. In this study, we have analyzed the regulation of the GluR1 subunit of the a-amino-3-hydroxy-5-methyl-4-isoxazole propionate glutamate receptor in the basal ganglia of primates following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopamine denervation. The dopamine denervation resulted in distinct alterations in GluR1 distribution: (1) GluR1 protein expression was markedly increased in caudate and putamen, and this was most pronounced in the striosomes; (2) GluR1 protein was altered minimally in subthalamic nucleus; (3) expression of GluR1 was down-regulated in the globus pallidus by 63% and in the substantia nigra by 57%. The down-regulation of GluR1 expression in the output nuclei of the basal ganglia, the internal segment of the globus pallidus and the substantia nigra pars reticulata, may be a compensation for the overactive glutamatergic input from subthalamic nucleus, which arises after striatal dopamine denervation. Our results indicate that the glutamatergic system undergoes regulatory changes in response to altered basal ganglia activity in a primate model of Parkinson's disease. Targeted manipulation of the glutamatergic system may be a viable approach to the symptomatic treatment of Parkinson's disease.
黑质纹状体多巴胺能去神经支配与基底神经节功能和神经化学解剖结构的复杂变化相关。兴奋性神经递质谷氨酸在该神经回路的关键点介导神经信号传递，且谷氨酸受体在基底神经节中呈差异分布。现有证据表明，黑质纹状体多巴胺耗竭后，谷氨酸能皮质纹状体和丘脑底核传出通路会变得过度活跃。在本研究中，我们分析了1-甲基-4-苯基-1,2,3,6-四氢吡啶诱导的多巴胺去神经支配后，灵长类动物基底神经节中α-氨基-3-羟基-5-甲基-4-异恶唑丙酸谷氨酸受体的GluR1亚基的调节情况。多巴胺去神经支配导致GluR1分布出现明显改变：（1）尾状核和壳核中GluR1蛋白表达显著增加，在纹状体小体中最为明显；（2）丘脑底核中GluR1蛋白变化最小；（3）苍白球中GluR1表达下调63%，黑质中下调57%。基底神经节输出核团，即苍白球内侧段和黑质网状部中GluR1表达的下调，可能是对纹状体多巴胺去神经支配后丘脑底核谷氨酸能输入过度活跃的一种代偿。我们的结果表明，在帕金森病灵长类模型中谷氨酸能系统会因基底神经节活动改变而发生调节性变化。对谷氨酸能系统进行靶向调控可能是帕金森病症状性治疗的一种可行方法。
