Synaptic Substrates of Age-Dependent Memory Deficits

年龄依赖性记忆缺陷的突触基质

• 批准号: 7118275
• 负责人: YURI GEINISMAN
• 金额: $ 33.92万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7118275
• 关键词: AMPA receptors; NMDA receptors; aging; animal old age; behavior test; behavioral /social science research tag; conditioning; electron microscopy; electrophysiology; hippocampus; histology; immunocytochemistry; laboratory rat; learning disorders; memory disorders; neural transmission; neurobiology; neurons; receptor expression; short term memory; synapses; voltage /patch clamp

DESCRIPTION (provided by applicant): Normal aging is commonly linked to a decline in learning and memory. It has long been known, however, that the age-related cognitive dysfunction does not affect all old individuals: some of them exhibit intact learning and memory capacities even at advanced chronological age. The reasons for such marked individual differences in mnemonic function during normal aging remain unknown, which hampers the development of therapeutic strategies for the prevention of age-related cognitive deficits. The aim of the proposed research is to evaluate the possibility of whether learning impairments in aged animals are associated with a reduction in the expression of AMPA and NMDA receptors (AMPARs; NMDARs) and in the magnitude of synaptic responses mediated by the receptors. The hippocampus-dependent learning task of trace eyeblink conditioning will be used to behaviorally characterize young and old rats and to separate the latter into learning-impaired and learning-unimpaired groups. Synapses will be examined in the hippocampus because its structural integrity is a prerequisite for successful acquisition of some forms of behavior and because this brain region is especially vulnerable to the process of aging. Immonocytochemically, levels of AMPAR and NMDAR immunoreactivity will be quantitatively evaluated at hippocampal synapses from the CA1 stratum radiatum with postembedding immunogold electron microscopy. The data to be obtained will demonstrate whether the proportion of putative postsynaptically silent synapses that lack AMPAR immunoreactivity is increased and the content of synaptic AMPARs and NMDARs is diminished only in learning-impaired rats. Electrophysiologically, AMPAR- and NMDAR-mediated responses will be pharmacologically isolated and quantitatively analyzed, using whole-cell voltage clamp recordings from CA1 pyramidal neurons made in hippocampal slices obtained from behaviorally characterized young and old rats. These data will show whether an increase in the number of functionally silent hippocampal synapses, as well as a reduction in the magnitude of AMPARs- and NMDAR-mediated synaptic responses occurs only in learning-impaired aged rats. If, as can be expected, the age related decline in cognitive function is found to be related to deficits in the expression of synaptic AMPARs and NMDARs and in their function, this would facilitate the design of preventive measures that make normal aging "successful."

描述（由申请人提供）：正常衰老通常与学习和记忆力下降有关。然而，人们早就知道，与年龄相关的认知功能障碍并不影响所有老年人：其中一些人即使在高龄时也表现出完整的学习和记忆能力。正常衰老过程中记忆功能存在如此显着个体差异的原因尚不清楚，这阻碍了预防与年龄相关的认知缺陷的治疗策略的开发。拟议研究的目的是评估老年动物的学习障碍是否与 AMPA 和 NMDA 受体（AMPAR；NMDAR）表达的减少以及受体介导的突触反应幅度的减少有关。微量眨眼条件反射的海马依赖性学习任务将用于表征年轻和年老大鼠的行为特征，并将后者分为学习障碍组和学习未障碍组。将在海马体中检查突触，因为其结构完整性是成功获得某些行为形式的先决条件，并且因为该大脑区域特别容易受到衰老过程的影响。通过免疫细胞化学方法，使用包埋后免疫金电子显微镜定量评估来自 CA1 放射层的海马突触的 AMPAR 和 NMDAR 免疫反应性水平。获得的数据将证明缺乏 AMPAR 免疫反应性的推定突触后沉默突触的比例是否增加，以及突触 AMPAR 和 NMDAR 的含量是否仅在学习障碍大鼠中减少。电生理学方面，AMPAR 和 NMDAR 介导的反应将使用从行为特征年轻和年老大鼠的海马切片中制作的 CA1 锥体神经元的全细胞电压钳记录进行药理学分离和定量分析。这些数据将显示功能性沉默海马突触数量的增加以及 AMPAR 和 NMDAR 介导的突触反应幅度的减少是否仅发生在学习障碍的老年大鼠中。如果正如可以预料的那样，发现与年龄相关的认知功能下降与突触 AMPAR 和 NMDAR 的表达及其功能缺陷有关，这将有助于设计预防措施，使正常衰老“成功”。