Subunit Changes in Aging NMDA Receptors Affect Memory

衰老 NMDA 受体亚基变化影响记忆

• 批准号: 7533344
• 负责人: KATHY R MAGNUSSON
• 金额: $ 26.54万
• 依托单位: OREGON STATE UNIVERSITY
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7533344
• 关键词: Accounting; Address; Adult; Affect; Age; Aging; Aging-Related Process; Alzheimer' s Disease; Anti-Inflammatory Agents; Anti-inflammatory; Area; Binding; Biological Models; Brain region; Cerebral cortex; Chromosome Pairing; Cognitive; Complex; DLG4 gene; Environment; Figs - dietary; Genes; Glutamate Receptor; Hippocampus (Brain); Human; Immunoprecipitation; Individual; Inflammation; Inflammatory; Intervention; Knowledge; Lead; Learning; Life; Lipopolysaccharides; Longevity; Memory; Memory impairment; Messenger RNA; Modeling; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Numbers; Pattern; Performance; Personal Satisfaction; Pharmaceutical Preparations; Prefrontal Cortex; Proteins; Public Health; RNA Splicing; Rate; Rodent; Role; Short-Term Memory; Sulindac; Synapses; Synaptic Membranes; Synaptosomes; TFAP2A gene; Testing; Therapeutic; Thick; Transgenic Mice; Ubiquitin; Variant; Viral Vector; Work; age effect; age related; aging brain; density; design; experience; functional decline; improved; juvenile animal; mRNA Expression; memory process; normal aging; presynaptic density protein 95; prevent; protein expression; psychologic; receptor; receptor binding; receptor expression; therapy design

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.

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。老年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）受体在幼年动物的空间记忆功能中非常重要。我们的特点是选择性的脆弱性NMDA受体的老化过程相比，其他谷氨酸受体在小鼠中。NMDA受体是多亚基复合体。ε 1（e1），ε 2（e2）和？1亚基在大脑皮层和海马中显著表达，这是对记忆至关重要的大脑区域。有证据表明，存在于老年大脑中的NMDA受体可能对记忆能力有害。还有待确定的是，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，还是老年大脑的环境使受体不再有益于记忆。在啮齿类动物中，在衰老过程中，e2亚基的蛋白质和mRNA表达下降幅度最大。年龄相关的NMDA受体结合密度下降似乎与E2 mRNA的减少有关。在前额叶皮层，衰老似乎对突触区域的e2蛋白表达有额外的影响。这是由于e2亚基与突触膜结合能力的改变还是蛋白质周转率的增加尚不清楚。什么？1亚基在衰老过程中表现出可变的变化。有证据表明消炎药能获益？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，或者炎症是否可以解释不同的模式。1剪接变异体的表达，发生在老化。该提案将解决的假设是，多种因素影响NMDA受体的特定亚基的表达模式，并导致与年龄相关的学习和记忆下降。该假设将通过以下三个具体目标来解决：1）为了确定增加老年大脑中e2亚基的表达是否有益于记忆性能，2）为了确定衰老如何改变影响记忆性能的突触环境中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中经历的记忆衰退产生影响。他们也应该是有用的阿尔茨海默氏症，因为它是叠加在衰老过程中。这些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了解。公共卫生相关性衰老过程中的记忆力下降对受影响的个人的心理和经济健康可能是非常昂贵的，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，改善整个生命周期的认知表现。