Heterogeneity of synaptic NMDA Receptors

描述(申请人提供)：纹状体传入和传出信息的微妙平衡控制着习得的运动行为的执行以及对不想要的动作的抑制。纹状体从皮质和丘脑接受谷氨酸能神经支配，从黑质接受多巴胺能神经支配，这两种神经递质相互调节功能，以维持适当的信息流出平衡，以顺利控制运动输出。纹状体的主要神经元类型是中棘神经元(MSN)，它是谷氨酸和多巴胺神经递质表达受体的接收者。本项目旨在比较N-甲基-D-天冬氨酸受体(NMDARs)受体介导的电流及其在纹状体苍白球和纹状体黑质MSN中介导电流的受体亚型。我们将利用从两个品系的小鼠制作的皮质纹状体切片，在D1或D2多巴胺受体表达细胞中选择性表达绿色荧光蛋白，以确定这些细胞中NMDA受体的独特性质。将利用皮质纹状体脑片中的单细胞电生理学来检验纹状体NMDA受体的一部分具有独特的性质并且在纹状体投射神经元的两个主要亚型之间分布不均的假设。根据初步数据显示，MSN表达一种亚型的NMDA通道，一旦被激活，该通道可以长时间重复开放和关闭，第一个特定目的是比较D2和D2 MSN突触和突触外NMDA受体的功能和药理，并验证NR1/NR2B/NR2D三种受体参与的假说。第二个目标将遵循激动人心的线索，即多巴胺耗竭和L-多巴治疗通过突触调节蛋白调节N-甲基-D-天冬氨酸受体亚型的分布，并将研究不同的多巴胺受体激活对N-甲基-D-天冬氨酸受体亚型的功能影响。公共卫生相关性：我们的研究结果将填补了解NMDA亚型谷氨酸受体在纹状体功能和运动控制中的作用的空白。鉴定表达不同多巴胺受体亚型的中等刺神经元中的NMDA受体将为回答一个基本问题提供一个独特的机会：多巴胺受体如何通过谷氨酸受体调节纹状体功能？这个问题的答案将对了解纹状体神经变性的病因学具有巨大的潜力，并将在NMDA受体家族中确定用于治疗运动障碍的新的治疗靶点。

DESCRIPTION (provided by applicant): A delicate balance of information to and from the striatum controls the execution of learned motor behaviors as well as the suppression of unwanted movements. The striatum receives converging glutamatergic innervation from the cortex and thalamus and dopaminergic innervation from the substantia nigra and these two neurotransmitters modulate the function of one another in order to maintain the proper balance of information outflow for smooth control of motor output. The main neuronal type in the striatum, the medium spiny neuron (MSN) is a recipient of these inputs express receptors for both glutamate and dopamine neurotransmitters. This project aims to compare N-methyl-D-aspartic acid receptors (NMDARs) receptor-mediated currents and the receptor subtypes that mediate them in striatopallidal versus striatonigral MSNs. We will utilize corticostriatal slices made from two strains of mice which selectively express green fluorescent protein in D1 or D2 dopamine receptor expressing cells to identify unique properties of NMDA receptors in these cells. Single cell electrophysiology in corticostriatal slices will be used to test the hypothesis that that a portion of striatal NMDA receptor have unique properties and are unequally distributed between the two major subtypes of striatal projection neurons. Based on preliminary data showing that MSN express a subtype of NMDA channel that once activated can open and close repetitively for a long time, the first specific aim will compare the function and pharmacology of synaptic and extrasynaptic NMDA receptors between D1 and D2 MSNs and will test the hypothesis of the involvement of the triheteromeric NR1/NR2B /NR2D receptors. The second aims will follow exciting leads that dopamine depletion and L-Dopa treatments regulate the distribution of NMDA receptor subtypes via synaptic regulatory proteins and will study the functional consequence of the activation of distinct dopamine receptors on NMDA receptor subtypes. PUBLIC HEALTH RELEVANCE: The results of our studies will fill a gap in the understanding of the role of NMDA subtype of glutamate receptor in striatal function and control of movements. Characterizing NMDA receptors in medium spiny neurons expressing distinct dopamine receptor subtypes will allow a unique opportunity to answer a fundamental question: How dopamine receptors regulate striatal function via glutamate receptors? This answer to this question will have great potential to understand the etiophatology of striatal neurodegeneration and will identify new therapeutic targets in the NMDA receptor family for treatment of movement disorders.