Synaptic Substrates of Age-Dependent Memory Deficits

描述(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：其中一些人即使在年事已高的时候也表现出完整的学习和记忆能力。在正常衰老过程中，记忆功能的个体差异如此显著的原因尚不清楚，这阻碍了预防年龄相关认知障碍的治疗策略的发展。这项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；NMDARs)的表达减少以及由该受体介导的突触反应的幅度有关。示踪眨眼条件反射的海马区依赖学习任务将被用来描述年轻和老年大鼠的行为特征，并将后者分为学习障碍组和学习非障碍组。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形式行为的先决条件，而且因为这个大脑区域特别容易受到衰老过程的影响。用免疫细胞化学方法，用包埋后免疫金电子显微镜对CA1放射层的海马区突触的AMPAR和NMDAR免疫反应性进行定量评价。将获得的数据将证明，是否只有在学习受损的大鼠中，缺乏AMPAR免疫反应的假定突触后沉默突触的比例增加，突触AMPAR和NMDAR的含量减少。电生理学上，AMPAR和NMDAR介导的反应将被分离出来，并使用全细胞电压钳记录进行定量分析，这些记录来自CA1锥体神经元的全细胞电压钳记录，这些神经元是从行为特征不同的年轻和老年大鼠的海马片中获得的。这些数据将表明，只有学习受损的老年大鼠才会出现功能沉默的海马区突触数量的增加，以及AMPAR和NMDAR介导的突触反应幅度的减少。如果正如可以预期的那样，与年龄相关的认知功能下降被发现与突触AMPAR和NMDARs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”。

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."