Subunit Changes in Aging NMDA Receptors Affect Memory

描述(申请人提供)：随着年龄的增长，人们遭受记忆力丧失的困扰，这干扰了他们的独立生活。发现衰老过程中记忆力下降的原因将使我们能够设计出既能延长老年生活质量又能延长老年生活安全的干预措施。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重要作用，已被证明在人类和啮齿动物中随着年龄的增长功能都会下降。我们发现，在衰老过程中，构成受体的一些亚单位的表达发生了变化，其中一些变化与记忆力下降有关。一个或多个亚基的变化可以改变NMDA受体的通道和药理学特性，这可能会改变受体对记忆过程做出贡献的整体能力。这一提议将解决的假设是，NMDA受体特定亚单位表达模式的复杂变化会导致与年龄相关的学习和记忆能力下降。该假说将通过以下四个具体目标来解决：1)确定不同大脑区域中与年龄相关的epsilon2亚单位表达下降的功能后果；2)确定与年龄相关的zeta1亚单位表达下降与空间记忆下降之间的关系是否与特定zeta1剪接变体的表达变化有关；3)确定受体亚单位蛋白突触表达的变化是否与衰老过程中空间记忆下降有关；4)区分三种可以增强认知能力的衰老干预措施(卡路里限制、学习体验和运动)对NMDA受体表达的影响。每个目标的行为测试将同时检查参考记忆和工作记忆。这些研究将提供信息，说明部分或完全恢复老年人记忆功能的干预措施是否应该旨在恢复年轻人和/或特定脑区中存在的特定NMDA受体亚单位的表达水平。这些结果将有助于我们努力改善正常衰老过程中的记忆功能，并有可能延缓阿尔茨海默病的一些衰退。这些信息还将增强我们对特定大脑区域中特定NMDA受体亚单位在学习和记忆中所起作用的了解。

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.