Subunit Changes in Aging NMDA Receptors Affect Memory

描述（由申请人提供）：随着年龄的增长，人们会失去记忆，无法独立生活。发现衰老过程中记忆衰退的原因将使我们能够设计出能够延长老年生活质量和安全的干预措施。n -甲基- d -天冬氨酸（NMDA）受体是谷氨酸受体的一种，在学习和记忆过程中起着重要作用，研究表明，随着人类和啮齿动物年龄的增长，其功能都会下降。我们发现，在衰老过程中，一些组成受体的亚基的表达发生了变化，其中一些变化与记忆力下降有关。一个或多个亚基的改变可以改变NMDA受体的通道和药理学特性，从而改变受体参与记忆过程的整体能力。该提案将解决的假设是，NMDA受体特定亚基表达模式的复杂变化导致与年龄相关的学习和记忆衰退。该假设将通过以下四个具体目标来解决：1)确定不同脑区epsilon2亚基表达随年龄变化而下降的功能后果；2)确定zeta1亚基表达随年龄变化与空间记忆衰退的关系是否与特定zeta1剪接变异体的表达变化有关；3)确定该受体亚基蛋白突触表达的变化是否与衰老过程中空间记忆衰退有关。4)区分三种衰老干预（热量限制、学习体验和运动）对NMDA受体表达的影响，这三种衰老干预均能增强认知能力。每个目标的行为测试都将检查参考记忆和工作记忆。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特定的NMDA受体亚基表达水平，这存在于年轻人和/或针对特定的大脑区域。这些结果将有助于我们在正常衰老过程中改善记忆功能，并有可能延缓阿尔茨海默病中出现的一些衰退。这一信息也将增强我们对特定大脑区域内特定NMDA受体亚基在学习和记忆中的作用的认识。

DESCRIPTION (provided by applicant): People suffer memory losses as they age that interfere with independent living. Discovering the causes for memory decline during the aging process will allow us to design interventions that can prolong both the quality and safety of life in old age. The N-methyl-D-aspartate (NMDA) receptor, a type of glutamate receptor, is important in learning and memory processes and has been shown to decline in function in both humans and rodents as they age. We have found changes during aging in the expression of some of the subunits that comprise the receptor and some of these changes are related to memory declines. Changes in one or more subunits can 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 that will be addressed by this proposal is that complex changes in the expression patterns of specific subunits of the NMDA receptor lead to age-related declines in learning and memory. The hypothesis will be addressed by the following four Specific Aims to: 1) Determine the functional consequences of the age-related decline in epsilon2 subunit expression within different brain regions, 2) Determine whether the relationship between age-related changes in the zeta1 subunit expression and spatial memory declines are associated with changes in the expression of specific zeta1 splice variants, 3) Determine whether changes in synaptic expression of the receptor subunit proteins are related to spatial memory declines during aging, 4) Differentiate the effects on NMDA receptor expression of three aging interventions (caloric restriction, learning experience, and exercise) that can each enhance cognitive abilities. Behavioral testing in each aim will examine both reference and working memory. These studies will provide information about whether interventions to partially or fully restore memory functions in aged individuals should be aimed at restoring specific NMDA receptor subunit expression levels that are present in the young and/or targeting specific brain regions. 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 within specific brain regions in learning and memory.