Regulation of Striatal Neurons by NMDA Receptor Subtypes

NMDA 受体亚型对纹状体神经元的调节

基本信息

批准号：
6609651
负责人：
KRISTEN A KEEFE
金额：
$ 28.5万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-15 至 2007-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Parkinson's Disease (PD) is a devastating movement disorder consequent to massive death of neurons in the substantia nigra. An important functional consequence of this cell death is depletion of the neuromodulator dopamine (DA) within the striatum. In addition to the DA input, the striatum also receives major glutamate input from the cerebral cortex and thalamus. The ameliorative effects of DA agonists in animal models of PD are potentiated by antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. In addition, NMDA antagonists block the appearance of dyskinesias in Parkinsonian animals treated with DA agonists and also block DA agonist and antagonist-induced immediate early gene expression in the intact striatum. Recent data from our laboratory indicate that distinct NMDA receptors selectively interact with Dl and D2 DA receptors to regulate immediate early gene expression in striatonigral and striatopallidal efferent neurons in both DA-depleted and intact animals. Furthermore, evidence suggests that corticostriatal and thalamostriatal afferents selectively affect the function of D2 receptor-containing striatopallidal and Dl receptor-containing striatonigral neurons, respectively. Finally, data from studies on other brain regions indicate that different NMDA receptor subtypes can be targeted to synapses associated with distinct afferent pathways within the same neuron. Thus, the goal of this proposal is to test the hypothesis that Dl and D2 dopamine receptors selectively interact with distinct NMDA receptors by virtue of the afferent-selective expression of distinct post-synaptic NMDA receptors in striatal efferent neurons. This hypothesis will be tested by completing the following specific aims: A) Establish how generalized the selective association of specific NMDA and DA receptors is across striatal efferent neuron responses. B) Determine the pharmacology of NMDA receptors mediating corticostriatal and thalamostriatal activation of immediate early gene expression in striatal efferent neurons in vivo and examine the modulation of this activation by DA receptor manipulations. C) determine the kinetics and pharmacology of NMDA receptor-mediated EPSCs evoked in striatal efferent neurons by activation of cortical and thalamic afferents and examine the modulation of those EPSCs by DA receptor manipulations. It is anticipated that the results of these experiments will provide new insight into the functional relationship between DA and NMDA receptors in the regulation of striatal efferent neurons and will lead to important new advances in therapeutic interventions for the treatment of PD and other disorders of the basal ganglia.

描述（由申请人提供）：帕金森氏病（PD）是一种毁灭性的运动障碍，造成黑质神经元的大规模死亡。该细胞死亡的一个重要功能后果是纹状体内神经调节剂多巴胺（DA）的耗竭。除了DA输入外，纹状体还从大脑皮层和丘脑中接收主要的谷氨酸输入。 DA激动剂在PD动物模型中的改善作用是由谷氨酸受体N-甲基-D-天冬氨酸（NMDA）亚型的拮抗剂增强的。此外，NMDA拮抗剂阻止了用DA激动剂治疗的帕金森氏症动物中运动障碍的出现，并阻止了DA激动剂和拮抗剂诱导的完整纹状体中的早期基因表达。我们实验室的最新数据表明，不同的NMDA受体选择性地与DL和D2 DA受体相互作用，以调节DA脱氧和完整动物中纹状体和纹状体胶质传出神经元中的早期基因表达。此外，有证据表明，皮质纹状体和丘脑纹状体传入分别有选择地影响含D2受体的含DL受体和DL受体的纹状体神经元的功能。最后，来自其他大脑区域的研究的数据表明，不同的NMDA受体亚型可以针对与同一神经元内不同传入途径相关的突触。因此，该提案的目的是检验以下假设：DL和D2多巴胺受体通过在纹状体传出神经元中独特的突触后NMDA受体的传入选择性表达选择性地与不同的NMDA受体相互作用。该假设将通过完成以下特定目的来检验：a）确定特定NMDA和DA受体的选择性关联如何跨纹状体传出神经元反应。 b）确定介导纹状体传出神经元中早期基因表达的NMDA受体的药理学，介导了体内纹状体传出神经元的早期基因表达，并检查了DA受体操作对这种激活的调节。 c）通过激活皮质和丘脑传入，确定在纹状体传出神经元中引起的NMDA受体介导的EPSC的动力学和药理学，并通过DA受体操作检查了这些EPSC的调节。预计这些实验的结果将为调节纹状体传出神经元的DA和NMDA受体之间的功能关系提供新的见解，并将导致治疗PD和其他基底神经节的其他疾病的治疗干预措施的重要新进展。