Synaptic Substrates of Age-Dependent Memory Deficits

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Learning and memory impairments often accompany aging. Frequently, such impairments are related to agerelated dementias. A substantial proportion of these, however, are attributable to so-called normal aging. Normal age-related cognitive dysfunction is most apparent in hippocampus-dependent behaviors. Interestingly, however, some aged individuals exhibit intact mnemonic function, whereas others are severely impaired, despite being the same chronologic age. Though the behavioral and physiological deficits associated with agerelated cognitive decline are well characterized, the substrates for such individual variability remain unknown. The aim of the proposed research is to evaluate the possibility that hippocampal synapses in aged impaired animals are gradually weakened such that distal synapses no longer have the same influence on neuronal output as more proximal ones. The proposed degradation of distance-dependent synaptic scaling in aged impaired animals would significantly disrupt synaptic integration and consequently impair hippocampal function. The basic strategy of the proposed research is to diagnose aged rats as either impaired or unimpaired using two hippocampus-dependent tasks, and then examine the morphology, receptor expression, function, and plasticity of their synapses in hippocampal CA1 pyramidal neurons. Rats will be behaviorally characterized using the Morris water maze and trace eyeblink conditioning, which assay spatial and temporal learning, respectively. The analyses of synapses will be accomplished by combining conventional and immunogold serial section electron microscopy with whole-cell patch-clamp recordings from CA1 pyramidal neurons. The major prediction is that the proportion or number of perforated synapses in aged impaired rats relative to aged unimpaired rats will be reduced, and this will be accompanied by a reduction in the expression of synaptic AMPA-type and NMDA-type receptors, particularly among distal synapses. The whole-cell patchclamp recordings will determine whether distal synapses and proximal synapses have the same influence on neuronal output in aged unimpaired rats, and whether such location-independence is disrupted in their aged impaired counterparts. Finally, an examination of the induction and reversal of long-term potentiation and depression in behaviorally characterized aged rats will provide insight into whether dysfunctional synaptic regulation contributes to the proposed reduction in distance-dependent synaptic scaling, and whether it correlates with age-related cognitive decline. All together, the experiments in this proposal will provide fundamental insights into synapses in the aging brain, and whether their form and function relate to cognitive capacity. Additionally, determining the nature and locus of deficient synaptic function in aged animals will facilitate the design of preventative measures intended to make aging more "succesful".