Synaptic Substrates of Age-Dependent Memory Deficits

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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."