Aging and dementia are often accompanied by diminished ability to learn and remember new information. Importantly, defects in memory play major roles in producing impairments in daily living and loss of functional independence. One strategy to improve the quality of life for the elderly is to develop treatments that improve memory function. Achieving this goal will require better understanding of cellular mechanisms involved in memory and how these mechanisms change with aging. Although the mechanisms involved in learning are not certain, it is believed that memory formation involves persistent use-dependent changes in synaptic function and that the long-term potentiation (LTP) of synaptic transmission that occurs following brief high-frequency use of excitatory synapses represents a model for memory-related synaptic plasticity. It also appears that the ability to induce LTP diminishes with aging and that mechanisms used early in life to generate LTP may not be as effective in the aged brain. In this proposal, we will use in vitro hippocampal slices prepared from rats of various postnatal ages ranging from adolescence through late adulthood to determine how LTP induction and expression change as a function of aging. Preliminary studies suggest that N-methyl-D-aspartate receptor (NMDAR)-dependent LTP in the CAl hippocampal region declines with aging, while LTP dependent upon voltage-activated Ca2+ channels (VACCs) persists. Furthermore, NMDAR-dependent LTP can be induced in the aging hippocampus provided that appropriate energy sources and/or neuromodulators are supplied. This project will build upon these preliminary observations and will address two specific aims: 1. To examine changes in LTP induction threshold and the role of NMDARs and VACCs during aging; 2. To examine the role of glucose, alternative energy substrates and insulin in modulating LTP induction with aging. It is hoped that better understanding of age-related changes in LTP and identifying ways to enhance NMDAR-dependent LTP in the adult hippocampus will lead to more effective treatments for age-related cognitive decline.
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