SUBUNIT CHANGES IN AGING NMDA RECEPTORS AFFECT MEMORY

老化 NMDA 受体亚基变化影响记忆

• 批准号: 6532511
• 负责人: KATHY R MAGNUSSON
• 金额: $ 19.16万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6532511
• 关键词: NMDA receptors; RNase protection assay; age difference; aging; binding sites; cerebral cortex; gene expression; in situ hybridization; laboratory mouse; memory; messenger RNA; receptor expression; western blottings

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.

描述（改编自申请人的摘要）：人类经历的下降， 随着年龄的增长，记忆力的表现。其中一些下降是良性的， 会影响独立生活解释记忆的原因 在衰老过程中的衰退将使我们能够设计干预措施， 延长老年生活的质量和安全。N-甲基-D-天冬氨酸 NMDA受体是谷氨酸受体的一种亚型，在学习和 记忆过程，并已被证明在人类和 随着年龄的增长，NMDA投标地点似乎更容易受到 衰老过程中比其他离子型谷氨酸受体和其他结合位点 对NMDA受体复合物的影响及大脑皮质吻端的变化 与记忆功能下降有关一个可能的解释是 可能是NMDA受体复合物亚基组成的变化 在老化过程中。一个或多个亚单位的变化可能会改变通道， NMDA受体的药理学特性，这可能会改变整体 受体对记忆过程的作用。的假设 该提案所解决的问题是，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 过程该假设将通过以下四个具体目标来解决 目的：1）确定NMDA亚基的mRNA表达是否有变化 在老化过程中通过使用原位杂交和核酸酶保护测定。（二） 确定NMDA亚基蛋白表达是否有变化 在老化过程中通过进行半定量Western印迹。3)确定 年龄相关的NMDA亚基表达变化是否与 通过比较mRNA和蛋白质结果与参考值， （Morris水迷宫）和工作（Olton径向臂迷宫）记忆任务。四、 确定是否抑制幼年动物中NMDA亚基的表达 在老年动物中观察到类似的记忆表现缺陷 通过注射反义寡核苷酸和记忆测试这些 研究将提供有关干预措施是否部分或 完全恢复老年人的记忆功能应该旨在恢复 NMDA受体亚单位的表达，这是目前在年轻人。这些 结果将有助于我们在正常情况下改善记忆功能的努力。 并可能延缓老年痴呆症的一些衰退 疾病这一信息也将增进我们对以下方面作用的了解： 在学习和记忆过程中的特定NMDA受体亚单位。