Heterogeneity of synaptic NMDA Receptors

纹状体控制区信息的微妙平衡 执行习得的运动行为以及抑制不受欢迎的行为 动静。纹状体接受会聚的谷氨酸能神经支配。 皮质、丘脑和黑质和丘脑的多巴胺能神经支配 这两种神经递质相互调节功能，以便 保持信息流出的适当平衡，以实现电机的平稳控制 输出。纹状体的主要神经元类型是中棘神经元(MSN) 是这些信息的接受者，表达谷氨酸和多巴胺的受体 神经递质。 该项目旨在比较N-甲基-D-天冬氨酸受体(NMDAR) 受体介导的电流及其受体亚型 纹状体甲状旁腺素与纹状体黑质MSN。我们将利用皮质纹状体切片 由两个品系的小鼠制成，它们选择性地表达绿色荧光 蛋白在细胞中表达多巴胺受体的特异性鉴定 这些细胞中NMDA受体的特性。单细胞电生理学研究 皮质纹状体切片和原代神经元培养将用于测试 假设纹状体NMDA受体的一部分具有独特的特性 在纹状体的两个主要亚型之间分布不均 投射神经元。 基于初步数据显示MSN表达NMDA的一个亚型 一旦激活，通道可以长时间反复打开和关闭， 第一个特定的目标是比较突触和药理的功能 突触外NMDA受体是D1MSN和D2MSN，并将测试 三异构体NR1/NR2B/NR2D受体参与的假说。 第二个目标将遵循激动人心的线索，即多巴胺枯竭和L-多巴 治疗通过突触调节NMDA受体亚型的分布 并将研究激活该蛋白的功能后果 NMDA受体亚型上不同的多巴胺受体。项目叙事。我们的研究结果将填补这方面的空白 谷氨酸受体NMDA亚型在纹状体中的作用 动作的功能和控制。培养上清液中NMDA受体的特性 表达不同多巴胺受体亚型的刺状神经元将允许独特的 回答一个基本问题的机会：多巴胺受体如何 通过谷氨酸受体调节纹状体功能？这个问题的答案是 将有很大的潜力来理解分层的病因 神经退行性变并将在NMDA中寻找新的治疗靶点 治疗运动障碍的受体家族。

ABSTRACT 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 and in primary neuronal cultures 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 repetetively for a long time, the first specific aim will compare the funtion and pharmacology of synaptic and extrasynaptic NMDA receptors bewteen 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 subytpes. Project NARRATIVE. 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 subytpes will allow a unique opportunity to answer a fundamental question: How dopamine receptors regulates striatal function via glutamate receptors? This answer to this question will have great potential to understand the etiophatology of stratial neurodegeneration and will identify new therapeutic targets in the NMDA receptor family for treatment of movement disorders.