Regulation of Striatal Neurons by NMDA Receptor Subtypes

描述(申请人提供)：帕金森病(PD)是一种毁灭性的运动障碍，导致黑质神经元的大量死亡。这种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)的枯竭。除了DA输入，纹状体还接受来自大脑皮层和丘脑的主要谷氨酸输入。多巴胺激动剂对帕金森病动物模型的改善作用可被谷氨酸受体的N-甲基-D-天冬氨酸(NMDA)亚型拮抗剂增强。此外，NMDA拮抗剂可阻止DA激动剂治疗的帕金森病动物出现运动障碍，也可阻断DA激动剂和拮抗剂诱导的完整纹状体即刻早期基因表达。我们实验室的最新数据表明，在DA缺乏和完整的动物中，不同的NMDA受体选择性地与DL和D2DA受体相互作用，调节纹状体黑质和纹状体苍白质传出神经元的即刻早期基因表达。此外，有证据表明，皮质纹状体和丘脑纹状体传入分别选择性地影响含D2受体的纹状体皮质神经元和含DL受体的纹状体黑质神经元的功能。最后，来自其他大脑区域的研究数据表明，不同的NMDA受体亚型可以针对与同一神经元内不同传入路径相关的突触。因此，本研究的目的是验证这一假设，即D1和D2多巴胺受体通过纹状体传出神经元中不同的突触后NMDA受体的传入选择性表达而选择性地与不同的NMDA受体相互作用。这一假设将通过完成以下具体目标来检验：a)确定特定NMDA和DA受体的选择性关联在纹状体传出神经元反应中的广泛性。B)确定NMDA受体在体内介导皮质纹状体和丘脑纹状体对纹状体传出神经元即刻早期基因表达的激活的药理作用，并检测DA受体对这种激活的调节作用。C)测定NMDA受体介导的EPSCs在纹状体传出神经元中的动力学和药理学作用，并研究DA受体对这些EPSCs的调节作用。预计这些实验结果将为DA和NMDA受体在调节纹状体传出神经元中的功能关系提供新的见解，并将在治疗帕金森病和其他基底节疾病的治疗干预方面取得重要的新进展。

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.