GLUTAMATE RECEPTORS, LONG TERM POTENTIATION AND AGING

谷氨酸受体、长期增强和老化

• 批准号: 6098493
• 负责人: CHARLES F ZORUMSKI
• 金额: $ 11.17万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2000-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098493
• 关键词: NMDA receptors; acetylcholine; action potentials; age difference; aging; albino rat; arachidonate; behavior test; biological signal transduction; calcium; divalent cations; dopamine; electrophysiology; excitatory aminoacid; gamma aminobutyrate; glutamate receptor; hippocampus; inositol phosphates; long term potentiation; memory; nitric oxide; norepinephrine; second messengers; tetany; voltage /patch clamp

The mechanisms underlying human memory are poorly understood but of importance to understanding the pathophysiology of Alzheimer's disease (AD) and other neurodegenerative disorders. Currently it is believed that memory involves changes in the efficacy of synaptic transmission and that long-term potentiation (LTP), a long-lived use-dependent enhancement of synaptic responses which follows brief high frequency activation of certain neural pathways, is a potential physiological process involved in memory. In certain regions of the central nervous system, LTP is critically dependent on activation of N-methyl-D-aspartate (NMDA) receptors and the influx of calcium into postsynaptic neurons. Calcium, in turn, is thought to activate a cascade of biochemical events leading to the pre- and postsynaptic changes which enhance synaptic transmission. Relevant to the memory deficits of dementing illnesses, a number of fundamental questions about LTP remain. These include uncertainties regarding how LTP changes as a function of aging, how changes in the extracellular concentration of excitatory amino acids (EAA) which can vary with disease state affect LTP, and whether modulatory transmitter systems which are altered in neurodegenerative diseases are involved in LTP at various ages. in the proposed studies we will investigate these issues using intra- and extracellular electrophysiological recordings from the CA1 region of in vitro rat hippocampal slices. In the first set of experiments we will examine the role of NMDA and metabotropic glutamate receptors in LTP in hippocampal slices prepared from rats of various postnatal ages, ranging from neonates to aged adults. A second set of experiments will examine the effects of low-level activation of EAA receptors on LTP generation. These studies will extend our preliminary observation that low micromolar concentrations of NMDA block LTP if given in the period immediately preceding or following high frequency synaptic stimulation. Finally, we will examine whether certain neuromodulators participate in LTP as a function of aging and whether these neuromodulators alter the NMDA-mediated inhibition of LTP. In these studies we will concentrate on norepinephrine, acetylcholine and dopamine, transmitter systems known to innervate the CA1 region and known to be affected in AD. These studies have the potential to provide information concerning the effects of aging on LTP generation and possibly on the memory deficits in dementing illnesses.

人们对人类记忆背后的机制知之甚少，但 了解阿尔茨海默病病理生理学的重要性 （AD）和其他神经退行性疾病。目前认为 记忆涉及突触传递效率的变化 长时程增强（LTP），一种长期使用依赖的增强作用 短暂的高频激活后的突触反应 某些神经通路，是参与的潜在生理过程 记忆。在中枢神经系统的某些区域，LTP 严重依赖于 N-甲基-D-天冬氨酸 (NMDA) 的激活 受体和钙流入突触后神经元。钙，在 转，被认为会激活一系列生化事件，从而导致 突触前和突触后的变化增强了突触传递。 与痴呆症的记忆缺陷有关，许多 关于 LTP 的基本问题仍然存在。其中包括不确定性 关于 LTP 如何随着年龄的增长而变化， 兴奋性氨基酸 (EAA) 的细胞外浓度可能会有所不同 疾病状态是否影响 LTP，以及调节递质系统是否 在神经退行性疾病中发生改变的 LTP 涉及 各个年龄段。在拟议的研究中，我们将调查这些问题 使用细胞内和细胞外电生理记录 体外大鼠海马切片的 CA1 区。在第一组中 我们将通过实验检验 NMDA 和代谢型谷氨酸的作用 不同大鼠海马切片中 LTP 受体的检测 出生后年龄，范围从新生儿到老年人。第二组 实验将检验低水平 EAA 激活的影响 LTP 生成的受体。这些研究将扩展我们的初步研究 观察到低微摩尔浓度的 NMDA 会阻断 LTP（如果给予） 在高频突触之前或之后的时期 刺激。最后，我们将检查某些神经调节剂是否 参与 LTP 作为衰老的函数，以及这些是否 神经调节剂改变 NMDA 介导的 LTP 抑制。在这些 我们将集中研究去甲肾上腺素、乙酰胆碱和多巴胺， 已知神经支配 CA1 区域的发射系统 受AD影响。这些研究有可能提供信息 关于衰老对 LTP 生成的影响以及可能对 痴呆症中的记忆缺陷。