Regulation of Striatal Neurons by NMDA Receptor Subtypes

描述（由申请人提供）：帕金森病（PD）是一种由黑质神经元大量死亡导致的破坏性运动障碍。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）的耗竭。除了DA输入外，纹状体还接收来自大脑皮层和丘脑的主要谷氨酸输入。谷氨酸受体n -甲基- d -天冬氨酸（NMDA）亚型拮抗剂增强了DA激动剂在PD动物模型中的改善作用。此外，NMDA拮抗剂可阻断DA激动剂治疗的帕金森病动物运动障碍的出现，并可阻断DA激动剂和拮抗剂诱导的完整纹状体中即时早期基因表达。我们实验室最近的数据表明，在DA缺失和完整的动物中，不同的NMDA受体选择性地与Dl和D2 DA受体相互作用，以调节纹状体和纹状顶输出神经元的早期基因表达。此外，有证据表明皮质纹状体和丘脑纹状体的传入事件分别选择性地影响含有D2受体的纹状体和含有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数据表明，不同的NMDA受体亚型可以靶向与同一神经元内不同传入通路相关的突触。因此，本研究的目的是验证Dl和D2多巴胺受体通过纹状体传出神经元突触后不同NMDA受体的传入选择性表达与不同NMDA受体选择性相互作用的假设。这一假设将通过完成以下具体目标来验证：A)确定特定NMDA和DA受体在纹状体输出神经元反应中的选择性关联有多普遍。B)确定NMDA受体介导纹状体输出神经元皮质纹状体和丘脑纹状体即刻早期基因表达激活的药理学，并检查DA受体操纵对这种激活的调节。C)通过激活皮质和丘脑传入神经，确定纹状体传出神经元中NMDA受体介导的EPSCs的动力学和药理学，并检查DA受体对这些EPSCs的调节。预计这些实验结果将对DA和NMDA受体在纹状体输出神经元调控中的功能关系提供新的认识，并为PD等基底神经节疾病的治疗干预带来重要的新进展。

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.