Synaptic Substrates of Age-Dependent Memory Deficits

年龄依赖性记忆缺陷的突触基质

• 批准号: 6951397
• 负责人: YURI GEINISMAN
• 金额: $ 34.28万
• 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/6951397
• 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的老年人：他们中的一些人甚至在高龄时也表现出完整的学习和记忆能力。在正常衰老过程中记忆功能的这种显著个体差异的原因仍然未知，这阻碍了预防与年龄相关的认知缺陷的治疗策略的发展。拟议的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（AMPARs; NMDARs）的表达减少以及受体介导的突触反应的幅度有关的可能性。将使用微量眨眼条件反射的校园依赖性学习任务来行为表征年轻和老年大鼠，并将后者分为学习受损和学习未受损组。突触将在海马体中进行检查，因为它的结构完整性是成功获得某些行为形式的先决条件，并且因为这个大脑区域特别容易受到衰老过程的影响。免疫组化，AMPAR和NMDAR免疫反应性的水平将定量评估海马突触从CA 1层辐射与植入后免疫金电子显微镜。所获得的数据将证明是否假定的突触后沉默的突触，缺乏AMPAR免疫反应性的比例增加，突触AMPAR和NMDAR的内容减少，只有在学习受损的大鼠。电生理学，AMPAR和NMDAR介导的反应将被分离和定量分析，使用全细胞电压钳记录从海马切片中获得的CA 1锥体神经元从行为特征的年轻和老年大鼠。这些数据将显示是否增加功能沉默的海马突触的数量，以及减少AMPAR和NMDAR介导的突触反应的幅度只发生在学习受损的老年大鼠。如果如预期的那样，发现与年龄相关的认知功能下降与突触AMPAR和NMDAR的表达及其功能的缺陷有关，这将有助于设计使正常衰老“成功”的预防措施。"