FUNCTIONAL NMDA RECEPTOR CHANGES IN PREFRONTAL CORTEX

记忆力丧失是一个重要的医学和社会问题，在我们的老龄化 社会 工作记忆是记忆的一种形式， 随着年龄的增长，人们知道人类和动物依赖于 前额叶皮层的执行功能， 工作记忆任务 更好地理解细胞和 老化过程中前额皮质的分子功能障碍 对前额叶功能的影响，比如工作记忆， 从而更好地干预与年龄相关的记忆衰退。 N- 甲基-D-天冬氨酸（NMDA）受体，已知在学习中很重要 和记忆过程，显示额叶皮层的递质结合减少， C57 B1/6小鼠的皮质区域（包括前额叶区域）， 与空间记忆衰退有关。 天然NMDA受体是 由多种类型的亚基组装而成， 受体的组成可以影响电生理和 受体的药理学特性。 的mRNA表达 ε 2（ε 2）亚基似乎显着减少， 老化小鼠大脑的额叶区域，类似于结合 变化 该提案旨在研究功能性 NMDA受体亚基组成变化的后果， 衰老的动物，并解决功能变化的假设， 在衰老过程中，NMDA受体亚基的变化引起的 组成，导致前额叶认知能力下降。 的 项目将1）描述空间工作记忆的表现， 3个不同年龄组（3、10和26个月）的小鼠，使用放射性 2）确定NMDA受体亚单位的表达组成 使用RT-PCR技术在来自相同小鼠的前额叶皮层中; 3） 确定老化对NMDA生物物理特性的影响 受体从这些小鼠使用双电极电压钳（TEVC） 非洲爪蟾卵母细胞表达系统上的技术;以及4）确定 衰老对NMDA受体药理学性质的影响， 再次对非洲爪蟾卵母细胞进行TEVC。目标1的结果 将与目标2-4中的目标进行比较。 的结果予以 研究应该提供一个机械的洞察我们的理解， 记忆力衰退 具体目标中提出的技术 数字2-4代表PI和采集的新方法 这些技术对于评估年龄的作用至关重要- NMDA受体的相关变化在老年人的记忆丧失中起作用。

Loss of memory is an important medical and social issue in our aging society. Working memory is one form of memory that shows declines with increasing age and it is known that humans and animals rely on the executive functions of the prefrontal cortex for proper performance of working memory tasks. A better understanding of the cellular and molecular dysfunctions that occur in the prefrontal cortex during aging and that impact on prefrontal functions, such as working memory, should lead to better interventions into age-related memory declines. The N- methyl-D-aspartate (NMDA) receptor, known to be important in learning and memory processes, shows decreases in transmitter binding in frontal cortical regions (including prefrontal regions) of C57B1/6 mice that are correlated with spatial memory declines. Native NMDA receptors are assembled from multiple types of subunits and differences in subunit composition of the receptor can influence the electrophysiological and pharmacological properties of the receptor. The mRNA expression of the epsilon2 (epsilon2) subunit appears to decrease significantly in the frontal regions of the aging mouse brain, similar to the binding changes. This proposal is designed to investigate the functional consequences of changes in NMDA receptor subunit composition in the aging animal and to address the hypothesis that functional changes during aging in the NMDA receptor, caused by changes in subunit composition, induce declines in prefrontal cognitive abilities. The project will 1) characterize the spatial working memory performance of 3 different age groups (3, 10, and 26 months) of mice using the radial arm maze; 2) confirm the expression of NMDA receptor subunit composition in the prefrontal cortex from the same mice using RT-PCR techniques; 3) determine the effect of aging on biophysical properties of the NMDA receptor from these mice using two-electrode voltage clamp (TEVC) techniques on a Xenopus oocyte expression system; and 4) determine the effect of aging on pharmacological properties of the NMDA receptor, again by performing TEVC on Xenopus oocytes. Results from Aim number 1 will be compared with those from Aims number 2-4. The results of these studies should provide a mechanistic insight into our understanding of memory loss during aging. The proposed techniques in Specific Aims number 2-4 represent new methodologies for the PI and the acquisition of these techniques is essential to the evaluation of the role that age- associated changes in NMDA receptors play in memory loss in the elderly.