Down‐regulation of metabotropic glutamate receptor 1α in globus pallidus and substantia nigra of parkinsonian monkeys
Down‐regulation of metabotropic glutamate receptor 1α in globus pallidus and substantia nigra of parkinsonian monkeys
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DOI：
10.1111/j.1460-9568.2005.04488.x
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发表时间：
2005-12
影响因子：
3.4
通讯作者：
K. Kaneda;Y. Tachibana;M. Imanishi;H. Kita;R. Shigemoto;A. Nambu;M. Takada
中科院分区：
文献类型：
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作者：
K. Kaneda;Y. Tachibana;M. Imanishi;H. Kita;R. Shigemoto;A. Nambu;M. Takada
增强的谷氨酸能神经传递通过丘脑下丘脑或丘脑下丘脑神经投射似乎是发展帕金森运动体征的关键。本研究对帕金森病灵长类动物基底神经节中代谢性谷氨酸受体（mGluRs）表达的可能变化进行了研究。与正常对照相比，通过系统注射1‐甲基‐4‐苯基‐1,2,3,6‐四氢吡啶（MPTP）对猕猴mGluR1α的免疫组织化学定位模式进行分析，我们发现白球内外节和网状黑质中mGluR1α的表达显著降低，而其他亚型的表达不明显。为了阐明mGluR1在控制苍白质神经元活动中的功能作用，我们对正常和帕金森猴进行了细胞外单位记录和细胞内显微注射mGluR1相关药物。在正常清醒状态下，白球复合体神经元的自发放电率被I组mGluRs的选择性激动剂DHPG增加，而AIDA （I组mGluRs的选择性拮抗剂）或LY367385 （mGluR1的选择性拮抗剂）降低。这些电生理数据有力地表明，谷氨酸对苍白叶神经元的兴奋机制至少部分是通过mGluR1介导的。在MPTP治疗后，mGluR1相关药物对内苍白球段神经元放电的影响变得相当模糊。我们的研究结果表明，帕金森状态下白垩质和黑质mGluR1α的特异性下调可能发挥代偿作用，以逆转疾病中产生的丘脑下核衍生的谷氨酸能输入的过度活跃。
Enhanced glutamatergic neurotransmission via the subthalamopallidal or subthalamonigral projection seems crucial for developing parkinsonian motor signs. In the present study, the possible changes in the expression of metabotropic glutamate receptors (mGluRs) were examined in the basal ganglia of a primate model for Parkinson's disease. When the patterns of immunohistochemical localization of mGluRs in monkeys administered systemically with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) were analysed in comparison with normal controls, we found that expression of mGluR1α, but not of other subtypes, was significantly reduced in the internal and external segments of the globus pallidus and the substantia nigra pars reticulata. To elucidate the functional role of mGluR1 in the control of pallidal neuron activity, extracellular unit recordings combined with intrapallidal microinjections of mGluR1‐related agents were then performed in normal and parkinsonian monkeys. In normal awake conditions, the spontaneous firing rates of neurons in the pallidal complex were increased by DHPG, a selective agonist of group I mGluRs, whereas they were decreased by AIDA, a selective antagonist of group I mGluRs, or LY367385, a selective antagonist of mGluR1. These electrophysiological data strongly indicate that the excitatory mechanism of pallidal neurons by glutamate is mediated at least partly through mGluR1. The effects of the mGluR1‐related agents on neuronal firing in the internal pallidal segment became rather obscure after MPTP treatment. Our results suggest that the specific down‐regulation of pallidal and nigral mGluR1α in the parkinsonian state may exert a compensatory action to reverse the overactivity of the subthalamic nucleus‐derived glutamatergic input that is generated in the disease.