GLUTAMATE RECEPTORS, LONG TERM POTENTIATION AND AGING

人类记忆背后的机制知之甚少，但 认识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，人们认为 记忆涉及突触传递效能的变化，而且 长时程增强(LTP)，一种长期使用依赖的增强 短暂高频激活后的突触反应 某些神经通路，是参与其中的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N-甲基-D-天冬氨酸(NMDA)的激活 受体和钙离子流入突触后神经元。钙，In 转而，被认为激活了一连串的生化事件，导致 突触前和突触后的变化，加强突触传递。 与痴呆症的记忆缺陷有关，一些 有关LTP的基本问题仍然存在。这些因素包括不确定性 考虑到LTP是如何作为老化的函数变化的， 兴奋性氨基酸(EAA)的胞外浓度可以变化 与疾病状态影响LTP，以及是否调制递质系统 在神经退行性疾病中改变的基因参与LTP 不同年龄的人。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 大鼠海马片的CA1区。在第一组 实验我们将研究NMDA和代谢性谷氨酸的作用 不同年龄组大鼠海马脑片LTP受体 出生后年龄，从新生儿到老年人。第二套 实验将检验低水平激活EAA的效果。 受体对LTP生成的影响。这些研究将延长我们初步的 观察到如果给予低微摩尔浓度的NMDA就会阻断LTP 在紧接高频突触之前或之后的时间段 刺激。最后，我们将检查某些神经调节剂是否 作为老化的函数参与LTP，以及这些 神经调节剂改变NMDA介导的对LTP的抑制。在这些 我们将集中研究去甲肾上腺素、乙酰胆碱和多巴胺， 已知支配CA1区的递质系统和已知的 在AD中受影响。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。

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.