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.

人类记忆的基本机制知之甚少， 了解阿尔茨海默病的病理生理学的重要性 (AD)和其他神经退行性疾病。目前据信， 记忆涉及突触传递功效的变化， 长时程增强（LTP），一种长寿命的使用依赖性增强 短暂的高频激活后的突触反应， 某些神经通路，是一个潜在的生理过程， 记忆在中枢神经系统的某些区域，LTP是 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。的钙 转，被认为激活了一系列生化事件， 增强突触传递的突触前和突触后变化。 与痴呆症的记忆缺陷有关， 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， 疾病状态影响LTP，以及是否调节递质系统 在神经退行性疾病中发生改变的神经元参与LTP， 不同年龄在拟议的研究中，我们将调查这些问题。 使用来自脑内和脑外的电生理记录， 体外大鼠海马脑片的CA 1区。的第一集合中 实验中，我们将研究NMDA和代谢型谷氨酸的作用， 受体的LTP在海马脑片制备从不同的大鼠 出生后年龄，从新生儿到老年人。第二组 实验将检查EAA的低水平激活的影响， 受体对LTP生成的影响。这些研究将扩大我们的初步 观察到低微摩尔浓度的NMDA阻断LTP， 在高频突触前或后的时期， 刺激.最后，我们将研究某些神经调质是否 参与LTP作为老化的功能，以及这些 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CA 1区域的递质系统， 受AD影响。这些研究有可能提供信息， 关于老化对LTP产生的影响， 痴呆症的记忆缺陷