Subunit Changes in Aging NMDA Receptors Affect Memory

描述：人类衰老的最早可察觉的后果之一是记忆功能的下降。造成这一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，因此它们可以作为一个模型系统。N-甲基-D-天冬氨酸(NMDA)受体在幼年动物的空间记忆功能中起重要作用。与小鼠的其他谷氨酸受体相比，我们研究了NMDA受体在衰老过程中的选择性易损性。NMDA受体是多亚单位复合体。Epsilon1(E1)、epsilon2(E2)和？1亚基在大脑皮层和海马区显著表达，这是大脑中对记忆至关重要的区域。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。是否是随着年龄的增长，表达的下降导致了剩余受体的有害影响，还是老化的大脑环境使受体不再对记忆有益，这一点仍有待确定。在啮齿动物的衰老过程中，e2亚单位的蛋白和mRNA的表达都出现了最大的下降。与年龄相关的NMDA受体结合密度的下降似乎与e2mRNA的这种下降有关。在前额叶皮质中，突触区域的e2蛋白表达似乎还受到了年龄的影响。目前尚不清楚这是由于e2亚单位与突触膜结合能力的改变，还是由于蛋白质周转率的增加。？1亚基在老化过程中表现出不同的变化。有证据表明，抗炎药物可以有益于？1和e2亚基的表达。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衰老过程中出现的不同剪接变体表达模式。这一提议将解决的假设是，多种因素影响NMDA受体特定亚单位的表达模式，并导致与年龄相关的学习和记忆下降。该假说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亚单位的表达是否有利于记忆表现；2)确定衰老如何改变e2亚单位在突触环境中的定位和联系，从而影响记忆表现；3)确定炎症是否导致与年龄相关的NMDA受体亚单位表达和记忆表现的下降。这些研究将对正常衰老过程中的记忆力衰退产生影响。它们对阿尔茨海默氏症也应该有用，因为它叠加在衰老过程中。这些信息还将增加我们对特定大脑区域中特定NMDA受体亚单位在学习和记忆过程中所起作用的了解。

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.