Heterogeneity of synaptic NMDA Receptors

描述（由申请人提供）：纹状体信息的微妙平衡控制着学习运动行为的执行以及对不想要的运动的抑制。纹状体接受来自皮质和丘脑的会聚性多巴胺能神经支配和来自黑质的多巴胺能神经支配，这两种神经递质调节彼此的功能，以维持信息流出的适当平衡，从而平稳地控制运动输出。纹状体中的主要神经元类型，中型多刺神经元（MSN）是这些输入的受体，表达谷氨酸和多巴胺神经递质两者的受体。本项目旨在比较N-甲基-D-天冬氨酸受体（NMDARs）受体介导的电流和受体亚型，介导他们在纹状体与纹状体黑质MSNs。我们将利用从两种小鼠品系中制备的皮质纹状体切片，其在D1或D2多巴胺受体表达细胞中选择性表达绿色荧光蛋白，以鉴定这些细胞中NMDA受体的独特性质。皮质纹状体切片中的单细胞电生理学将用于检验以下假设：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不均匀分布。基于初步数据显示MSN表达一种NMDA通道亚型，一旦激活，可以长时间重复打开和关闭，第一个具体目标将比较D1和D2 MSN之间突触和突触外NMDA受体的功能和药理学，并将测试三异聚体NR 1/NR 2B/NR 2D受体参与的假设。第二个目标将遵循令人兴奋的线索，即多巴胺耗竭和L-Dopa治疗通过突触调节蛋白调节NMDA受体亚型的分布，并将研究NMDA受体亚型上不同多巴胺受体激活的功能后果。公共卫生相关性：我们的研究结果将填补一个空白，在理解的作用，谷氨酸受体的NMDA亚型纹状体功能和控制的运动。表征中棘神经元表达不同的多巴胺受体亚型的NMDA受体将允许一个独特的机会来回答一个基本的问题：多巴胺受体如何通过谷氨酸受体调节纹状体功能？这个问题的答案将有很大的潜力，以了解纹状体神经变性的病因，并将确定新的治疗目标，在NMDA受体家族治疗运动障碍。

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.