HETEROGENEITY OF SYNAPTIC NMDA RECEPTORS

描述：N-甲基-D-天冬氨酸（NMDA）受体有助于 突触形成、学习记忆和神经系统疾病的发病机制 紊乱 NMDA受体分子克隆的最新进展， 揭示了这些受体的分子形式的实质异质性。 提出NMDA受体分子形式的异质性 兴奋性突触及其翻译后修饰， EM介导的突触传递的NMDA成分的有效性 进而影响突触可塑性。 特定的生理操作， 导致亚基表达差异和翻译后 修饰导致NMDA受体介导的突触 功能将被研究。 突触的功能多样性， 突触外NMDA在脑切片中的不同神经元群体中， 原代培养将采用电生理学、解剖学和生物学方法进行研究。 和药理学技术。 这项研究的结果将揭示如何 NMDA亚基NR 1和NR 2B的相对贡献决定了 发育中大鼠皮层神经元NMDA介导的突触电流动力学 和小脑神经元。 主要假设是， NR 1/NR 2A异聚体的数量是控制疗效的关键组分 突触NMDA受体。 重组受体将用于比较 并对比与神经元中观察到的功能差异， 为了理解在不同的生物体之间观察到的动力学差异的机制， 不同分子形式的NMDA受体。 初步结果与 重组受体表明，亚基组成不是唯一的 突触NMDA受体的动力学决定簇。 因此， 翻译后修饰在产生不同的突触动力学中的作用 将测定皮质神经元中的NMDA电流。 最后，实验 策略将用于调节不同的NMDA受体的表达， 新皮层和小脑神经元中的亚型， 了解神经元活动、蛋白激酶和神经营养因子 控制NMDA受体亚型的表达。 数据来源于这些 特定的目标将允许理解分子决定簇 负责CNS中的突触可塑性。

DESCRIPTION: N-Methyl-D-Aspartic acid (NMDA) receptors contribute to synapse formation, learning and memory and the pathogenesis of neurological disorders. Recent developments in molecular cloning of NMDA receptors have revealed a substantial heterogeneity of molecular forms of these receptors. It is proposed that the heterogeneity of molecular forms of NMDA receptors at excitatory synapses and their posttranslational modifications, underlie the effectiveness of the NMDA component of EM mediated synaptic transmission and in turn synaptic plasticity. Specific physiological manipulations that result in differential subunit expression and posttranslational modifications leading to alteration of NMDA receptor-mediated synaptic function will be studied. The functional diversity of synaptic and extrasynaptic NMDA in distinct neuronal populations in brain slices and primary culture will be investigated with electrophysiological, anatomical and pharmacological techniques. The result of this study will reveal how the relative contribution of the NMDA subunit NR1 and NR2B determines the kinetics of NMDA-mediated synaptic currents in developing rat neocortical and cerebellar neurons. The main hypothesis is that the relative proportion of NR1/NR2A heteromers are the crucial component that controls the efficacy of synaptic NMDA receptors. Recombinant receptors will be used to compare and contrast functional differences related to those observed in neurons and to understand mechanisms underlying the kinetic differences observed between different molecular forms of NMDA receptors. Preliminary results with recombinant receptors suggest that subunit composition is not the only kinetic determinant of synaptic NMDA receptors. Therefore, the role for posttranslational modifications in producing distinct kinetics of synaptic NMDA currents in cortical neurons will be determined. Lastly, experimental strategies will be used to regulate expression of distinct NMDA receptor subtypes in neocortical and cerebellar neurons resulting in the understanding of how neuronal activity, protein kinases and neurotrophins control the expression of NMDA receptor subtypes. Data obtained from these specific aims will permit the understanding of the molecular determinant responsible for synaptic plasticity in CNS.