NMDA RECEPTOR DEVELOPMENT IN NEOSTRIATUM

新纹状体中 NMDA 受体的发育

• 批准号: 6330493
• 负责人: Michael S. Levine
• 金额: $ 19.39万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-08 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6330493
• 关键词: AMPA receptors; Animalia; NMDA receptors; corpus striatum; developmental neurobiology; dopamine; electrophysiology; enzyme activity; glutamate receptor; immunocytochemistry; protein kinase; receptor binding; receptor expression; voltage gated channel

DESCRIPTION: This proposal addresses the functional development of glutamate receptors (GluRs) in the neostriatum (NS), concentrating on the N-methyl-d-aspartate (NMDA) receptor. NMDA receptors are considered one of the most important subtypes of GluRs and there is considerable evidence that nervous system development is critically dependent upon NMDA receptor function. Understanding developmental regulation of NMDA receptors is particularly important in the NS where control of motor programs and cognitive abilities are determined. The main driving force behind NS activation and the most important transmitter system in the NS is the Glu-containing system that originates from the cortex. This system makes monosynaptic contacts with all subtypes of NS cells, has a primary role in NS information processing, is implicated in use-dependent plasticity and during early developmental periods may have trophic influences. If Glu inputs and receptors are the prime activators of adult NS cells, the development of GluRs can be expected to have major implications for NS functioning during postnatal maturation. Experiments are designed to examine when GluRs become functional and when Glu-containing synapses make functional contacts on two subpopulations of NS cells, medium- and large-size cells. One hypothesis forms a framework for this proposal. It states that there are two age periods when NMDA receptor function in the NS will be particularly important, an early period [from postnatal days (PNDs) 7-14] as asymmetrical synapses are forming, and a later period (PNDs 20-22) at the end of the peak period of formation of corticostriatal synapses. To test this hypothesis, NMDA receptor development will be compared with that of (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate (KA) receptors in the two subpopulations of NS neurons. State-of-the-art electrophysiological methods in which cells in slices are visualized before and during whole cell clamp recordings will be used to assess the developmental alterations in GluR agonist-evoked currents. Mechanisms by which NMDA receptor function changes developmentally will be examined. These include development of voltage-dependence, development of receptor binding, development of mRNA and protein expression for GluR subunits, and development of modulation of NMDA receptor function by metabotropic GluRs, dopamine and protein kinases. In combination, complementary information will be integrated to provide a complete picture of the development of NS GluRs. The outcomes will provide information necessary to understand the role of these receptors in NS development and provide clues for generating rational strategies to treat GluR dysfunction during development and in the adult.

描述：本提案涉及以下方面的功能开发 谷氨酸受体（GluRs）在新纹状体（NS），集中在 N-甲基-D-天冬氨酸（NMDA）受体。 NMDA受体被认为是 最重要的GluRs亚型，有大量证据表明， 神经系统发育严重依赖于NMDA受体 功能 了解NMDA受体的发育调节是 在NS中尤其重要，其中控制运动程序和 认知能力是确定的。 NS背后的主要驱动力 激活和最重要的发射系统在NS是 源自大脑皮层的含谷氨酸系统。 该系统使 与NS细胞的所有亚型的单突触接触，具有主要作用， NS信息处理，涉及使用依赖的可塑性， 在早期发育阶段可能有营养影响。 如果Glu 输入和受体是成年NS细胞的主要激活剂， GluRs的发展可能对NS有重要意义 在出生后的成熟期发挥作用。 实验旨在 检查GluRs何时发挥功能，以及含Glu的突触何时使 在NS细胞的两个亚群上的功能性接触， 大型细胞。 一个假设构成了这一提议的框架。 它 指出，有两个年龄段时，NMDA受体功能的NS 将是特别重要的，早期[从出生后几天（PND） 7-14]作为不对称的突触正在形成，和后期（PND 20-22） 在皮质纹状体突触形成高峰期结束时。 到 为了验证这一假设，将NMDA受体的发育与 氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）和红藻氨酸 (KA)受体的两个亚群的NS神经元。 State-of-the-art 电生理学方法，其中切片中的细胞在 并且在全细胞钳夹记录期间将用于评估 GluR激动剂诱发电流的发育改变。 机制 将检测NMDA受体功能在发育过程中的变化。 这些包括电压依赖性的发展，受体的发展 GluR亚基的结合、mRNA和蛋白质表达的发展，以及 通过代谢型GluRs调节NMDA受体功能的发展， 多巴胺和蛋白激酶。 结合起来，补充信息 将被整合，以提供NS发展的完整画面 GluRs。 结果将提供必要的信息，以了解 这些受体在NS发展中的作用，并提供线索， 合理的策略来治疗发育过程中的GluR功能障碍， 成年人了