SUBUNIT CHANGES IN AGING NMDA RECEPTORS AFFECT MEMORY

描述(改编自申请者摘要)：人类经历在 随着年龄的增长，他们的记忆性能。其中一些下降是良性的，但也有一些 会干扰独立生活。阐明记忆产生的原因 衰老过程中的下降将使我们能够设计出能够 延长老年生活质量和安全。N-甲基-D-天冬氨酸 谷氨酸受体(NMDA)受体是谷氨酸受体的一种亚型，在学习和学习中起重要作用 记忆过程，并已被证明在人类和 啮齿动物随着年龄的增长。NMDA投标网站似乎更容易受到 衰老过程比其他离子型谷氨酸受体和其他结合部位 N-甲基-D-天冬氨酸受体复合体与吻侧大脑皮层的变化 与记忆功能下降有关。对此有一个潜在的解释 可能是NMDA受体复合体亚单位组成的变化 在衰老过程中。一个或多个亚基的变化可能会改变通道和 NMDA受体的药理学特性，它可以改变整体 受体对记忆过程做出贡献的能力。假说 该提案解决的问题是，与年龄相关的记忆力下降是由以下因素引起的 衰老过程中NMDA受体亚单位表达的变化 进程。这一假设将通过以下四个具体目标来解决 目的：1)确定NMDA亚单位的mRNA表达是否发生变化 用原位杂交和核酸酶保护试验检测。2) 确定NMDA亚单位蛋白的表达是否有变化 在老化过程中，通过执行半定量的Western blotting。3)确定 NMDA亚单位表达的年龄相关变化是否与 将mRNA和蛋白质结果与参考结果进行比较，空间记忆能力会下降 (Morris水迷宫)和工作(Olton放射臂迷宫)记忆任务。4) 确定是否抑制幼年动物NMDA亚单位(S)的表达 会导致与老年动物相似的记忆能力下降 使用反义寡核苷酸注射和记忆测试。这些 研究将提供关于干预措施是部分还是 完全恢复老年人的记忆功能应以恢复为目标 在年轻人中存在的NMDA受体亚单位的表达。这些 结果将有助于我们努力在正常情况下改善记忆功能 衰老过程，并可能延缓阿尔茨海默氏症的一些衰退 疾病。这些信息还将增强我们对 学习和记忆过程中特定的NMDA受体亚单位。

DESCRIPTION (Adapted from applicant's abstract): Humans experience declines in memory performance as they age. Some of these declines are benign, but others can interfere with independent living. Elucidating the causes for memory decline during the aging process will allow us to design interventions that can prolong the quality and safety of life in old age. The N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors, is important in learning and memory processes and has been shown to decline in function in both humans and rodents as they age. The NMDA biding site appears to be more vulnerable to the aging process than other ionotropic glutamate receptors and other binding sites on the NMDA receptor complex and the changes in the rostral cerebral cortex correlate with declines in memory function. One potential explanation for this could be a change in the subunit composition of the NMDA receptor complex during aging. Changes in one or more subunits could alter the channel and pharmacological properties of the NMDA receptor, which could alter the overall ability of the receptor to contribute to memory processes. The hypothesis addressed by the proposal is that age-related declines in memory are induced by changes in the expression of subunits for the NMDA receptor during the aging process. The hypothesis will be addressed by the following four Specific Aims to: 1) Determine whether there are changes in mRNA expression for NMDA subunits during aging by using in situ hybridization and nuclease protection assays. 2) Determine whether there are changes in the expression of NMDA subunit proteins during aging by performing semi-quantitative Western Blotting. 3) Determine whether age-related changes in NMDA subunit expression are associated with spatial memory declines by comparing mRNA and protein results with reference (Morris water maze) and working (Olton radial arm maze) memory tasks. 4) Determine whether inhibiting the expression of NMDA subunit(s) in young animals induces similar deficits in memory performance to those seen in aged animals with the use of antisense oligonucleotide injections and memory testing. These studies will provide information about whether interventions to partially or fully restore memory functions in aged individuals should be aimed at restoring the NMDA receptor subunit expression that is present in the young. These results will aid our efforts to improve memory functions during the normal aging process and potentially delay some of the declines seen in Alzheimer's disease. This information will also enhance our knowledge about the role of specific NMDA receptor subunits in learning and memory processes.