Subunit Changes in Aging NMDA Receptors Affect Memory

描述：人类衰老最早可检测到的后果之一是记忆功能下降。造成这种下降的因素尚不清楚。衰老的啮齿动物在空间记忆任务中表现出与人类相似的记忆功能衰退，因此它们可以用作模型系统。N-甲基- d -天冬氨酸（NMDA）受体在幼龄动物的空间记忆功能中起着重要作用。与其他谷氨酸受体相比，我们在小鼠中表征了NMDA受体对衰老过程的选择性脆弱性。NMDA受体是多亚基复合物。1 (e1) 2 （e2）还有？1亚基在大脑皮层和海马体中显著表达，这些区域对记忆至关重要。有证据表明，存在于老年人大脑中的NMDA受体可能对记忆能力有害。究竟是随着年龄的增长而减少的表达导致了剩余受体的有害影响，还是老年大脑的环境使受体不再对记忆有益，目前还有待确定。e2亚基在啮齿类动物衰老过程中蛋白和mRNA的表达下降幅度最大。NMDA受体结合密度的年龄相关性下降似乎与e2 mRNA的减少有关。在前额叶皮层，似乎有一个额外的影响，衰老对突触区域的e2蛋白表达。这是由于e2亚基与突触膜结合能力的改变，还是由于蛋白质周转率的增加，目前尚不清楚。的吗?1个亚基在老化过程中呈现可变变化。有证据表明，抗炎药物可以获益？1和e2亚基表达。目前尚不清楚这种情况发生的时间有多早，也不知道炎症是否可以解释这种不同的模式。1剪接变异体表达在衰老过程中发生。本研究提出的假设是，多种因素影响NMDA受体特定亚基的表达模式，并导致与年龄相关的学习和记忆能力下降。这一假设将通过以下三个具体目标来解决：1)确定增加老年大脑中e2亚基的表达是否有利于记忆表现，2)确定衰老如何改变影响记忆表现的突触环境中e2亚基的定位和关联，以及3)确定炎症是否有助于NMDA受体亚基表达和记忆表现的年龄相关下降。这些研究将对正常衰老过程中经历的记忆衰退产生影响。它们也应该对阿尔茨海默病有用，因为它是叠加在衰老过程中的。这一信息也将增加我们对特定大脑区域内特定NMDA受体亚基在学习和记忆过程中的作用的认识。随着年龄的增长，记忆力下降对受影响的个人的心理和经济健康可能会造成非常昂贵的代价，因为它会干扰他们独立生活的能力。了解衰老过程如何影响参与学习和记忆过程的分子，使我们能够更好地设计干预措施，提高整个生命周期的认知表现。

DESCRIPTION: One of the earliest detectable consequences of aging in people is a decline in memory functions. The factors that are responsible for this decline are not yet understood. Aging rodents show similar functional declines in memory as humans in spatial memory tasks, so they can be used as a model system. The N- methyl-D-aspartate (NMDA) receptor is very important in spatial memory functions in young animals. We have characterized a selective vulnerability of NMDA receptors to the aging process as compared to the other glutamate receptors in mice. NMDA receptors are multi-subunit complexes. The epsilon1 (e1), epsilon2 (e2), and ?1 subunits are prominently expressed in the cerebral cortex and hippocampus, brain regions that are critical for memory. There is evidence that the NMDA receptor that is present in the aged brain may be detrimental to memory abilities. It remains to be determined whether it is the decline in expression with age that leads to detrimental influences of the remaining receptors or whether it is the environment of the aged brain that makes the receptor no longer beneficial for memory. The e2 subunit shows the greatest declines in both protein and mRNA expression during aging in rodents. The age-related decline in NMDA receptor binding density appears to be related to this decrease in e2 mRNA. In the prefrontal cortex, there appears to be an additional effect of aging on e2 protein expression in the area of the synapse. Whether this is due to an alteration in the ability of the e2 subunit to associate with the synaptic membrane or an increased turnover rate of the protein is not known. The ?1 subunit shows variable changes during aging. There is evidence that anti- inflammatory drugs can benefit ?1 and e2 subunit expression. It is not known how early this occurs or whether inflammation can account for the different patterns of ?1 splice variant expression that occur during aging. The hypothesis that will be addressed by this proposal is that multiple factors influence the expression patterns of specific subunits of the NMDA receptor and lead to age-related declines in learning and memory. The hypothesis will be addressed by the following three Specific Aims: 1) To determine whether increasing the expression of the e2 subunit in the aged brain is beneficial to memory performance, 2) To determine how aging alters the localizations and associations of the e2 subunit within the synaptic environment that influence memory performance, and 3) To determine whether inflammation contributes to age-related declines in NMDA receptor subunit expression and memory performance. These studies will have implications for the memory declines experienced in normal aging. They should also be useful in Alzheimer's disease because it is superimposed on the aging process. This information will also add to our knowledge about the role of specific NMDA receptor subunits within specific brain regions on learning and memory processes. PUBLIC HEALTH RELEVANCE Memory declines during aging can be very costly to the psychological and financial well being of individuals that are affected because it can interfere with their ability to live independently. Understanding how the aging process affects molecules that are involved in learning and memory processes allows us to better design interventions that will improve cognitive performance throughout the lifespan.