AMINO ACID RECEPTORS AND BASAL GANGLIA FUNCTION

基底节在控制正常的运动和运动中起主要作用 协调。基底节的损害导致运动障碍 从严重的运动迟缓、僵硬和震颤到肌张力障碍、舞蹈症和 芭蕾舞剧。某一特定个体或疾病的症状学 这一过程取决于受影响的神经元的不同亚群。 基底节的神经化学和功能解剖现在是 正在做详细的工作。氨基酸类神经递质似乎 调节大多数基底节突触的神经传递。这个 抑制性氨基酸，GABA，是 纹状体、苍白球和黑质神经元占多数。兴奋的 氨基酸，如谷氨酸，是人体的神经递质。 皮质和丘脑传出至纹状体、丘脑底核和 黑质神经元。GABAA和EAA受体的亚型有 独特的药理作用和信号转导特性。此外， 其中许多受体亚型的基因已经被克隆。 间接证据表明，纹状体神经元最 易患亨廷顿病的患者表达更多的NMDA和代谢性EAA 而不是其他纹状体神经元的受体。这一假设将得到检验。 利用寡核苷酸探针的双标记原位杂交技术 这些受体和针对这些受体的抗体的免疫组化 受体蛋白。 在以前的研究中，我们发现GABAA的不同亚型 而EAA受体专门调节纹状体的反应， 皮质、黑质和丘脑下部受损。这项工作将扩展到 研究假设GABAA和非NMDA的特异性基因 选择性皮损后受体亚型的差异调节 基底节亚核。我们将结合配基放射自显影 与GABAA寡核苷酸探针的原位杂交结合， AMPA和亲代谢性受体亚基。我们预计，这些 在损伤后调节的受体可能不是那些 在正常情况下主要表达。澄清： 亨廷顿氏病动物模型中受体调节的细节 疾病，帕金森氏症，肌张力障碍和偏瘫将允许我们 为这些疾病设计更有效的药物疗法 对各种受体亚型有选择性的药物。这样的研究将 也增加了对健康和健康中的基底神经节回路的理解 疾病。

The basal ganglia play a major role in the control of normal movement and coordination. Lesions of the basal ganglia result in movement disorders ranging from severe akinesia, rigidity and tremor to dystonia, chorea and ballismus. The symptomatology in any particular individual or disease process depends on the distinct subgroups of neurons affected. The neurochemical and functional anatomy of the basal ganglia are now being worked out in detail. The amino acid neurotransmitters appear to mediate neurotransmission at a majority of basal ganglia synapses. The inhibitory amino acid, GABA, is the neurotransmitter for the vast majority of striatal, pallidal and substantia nigra neurons. Excitatory amino acids, (EAA) such as glutamate serve as the neurotransmitters for cortical and thalamic efferents to striatum, subthalamic nucleus and substantia nigra neurons. The subtypes of GABAA and EAA receptors have unique pharmacologies and signal transduction properties. Furthermore, the genes for many of these receptor subtypes have been cloned. Circumstantial evidence suggests that the striatal neurons most vulnerable in Huntington's disease express more NMDA and metabotropic EAA receptors than other striatal neurons. This hypothesis will be tested using double-label in situ hybridization of oligonucleotide probes for these receptors and immunohistochemistry of antibodies directed against the receptor proteins. In previous studies we have found that the different subtypes of GABAA and EAA receptors regulate specifically in response to striatal, cortical, nigral and subthalamic lesions. This work will be extended to investigate the hypothesis that the specific genes for GABAA and non-NMDA receptor subtypes regulate differentially after selective lesions of basal ganglia subnuclei. We will combine autoradiography of ligand binding with in situ hybridization of oligonucleotide probes for GABAA, AMPA, and metabotropic receptor subunits. We anticipate that those receptors that regulate after lesions may not be those that are predominantly expressed under normal conditions. Elucidation of the details of receptor regulation in these animal models of Huntington's disease, Parkinson's disease, dystonia, and hemiballismus will allow us to devise more effective pharmacotherapies for these illnesses using drugs selective for the various receptor subtypes. Such studies will also add to the understanding of basal ganglia circuitry in health and disease.