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的下降有关。然而，长期以来，众所周知，与年龄相关的认知功能障碍并不影响所有老年人：即使在高级年代年代，其中一些人也表现出完整的学习和记忆能力。正常衰老期间，这种明显的助记功能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。拟议研究的目的是评估老年动物学习障碍的可能性是否与AMPA和NMDA受体（AMPARS; NMDARS）表达的降低以及受体介导的突触反应的幅度有关。痕迹互联网调节的海马依赖性学习任务将在行为上表征年轻大鼠和老鼠，并将后者分为受学习障碍和学习不受影响的群体。突触将在海马中进行检查，因为其结构完整性是成功获得某些形式行为的先决条件，并且因为该大脑区域特别容易受到衰老的影响。在侵入化学上，将在来自Ca1辐射的海马突触上进行定量评估AMPAR和NMDAR免疫反应水平，并使用后置Immunogold电子显微镜进行定量评估。要获得的数据将证明缺乏AMPAR免疫反应性的突触后沉默突触的比例是否会增加，而突触AMPAR和NMDAR的含量仅在学习障碍的大鼠中会降低。在电生理学上，使用来自行为表征的年轻人和老鼠的海马切片中的CA1锥体神经元的全细胞电压夹记录，将在药理学上分离和定量分析药理学分离和定量分析。这些数据将显示功能静音海马突触的数量增加，以及减少AMPARS和NMDAR介导的突触反应的大小仅在学习障碍的老年大鼠中发生。如果可以预料，发现认知功能与年龄相关的下降与突触AMPAR和NMDAR的表达缺陷以及其功能有关，这将有助于设计正常衰老“成功”的预防措施的设计。