Decline in cognitive function is a critical concern during normal aging. The proposed research will study changes in the levels of synaptic proteins during aging, as well as the functional consequences of those changes. In addition, studies will determine the relationship between these measures and variations in the GH/IGF-1 axis. The proposed studies will utilize a rodent model of aging, the Fisher 344 X Brown Norway (F344XBN). F344XBN rats demonstrate an aging-related decline in learning and memory accompanied by changes in subunit levels of AMPA and NMDA types of the glutamate receptor in the hippocampus, a brain region closely linked to memory consolidation. Infusion of IGF-1 not only ameliorates the aging-related decline in learning and memory, it also increases the incidence of multiple spine bouton synapses that have been associated with an increased presence of glutamate receptors as well as enhanced long term potentiation (LTP), thought to be a physiological correlate of learning and memory. Proposed studies will address the issue of what role the GH/IGF-1 axis plays in the maintaining synaptic proteins across life span. In addition, studies will examine whether there are functional consequences in the protein level changes and whether growth hormone supplementation alleviates these age-related declines in synaptic proteins and alterations in function. The overall hypothesis is that age-related changes in the GH/IGF-1 axis mediate alterations in the composition and function of synapses in the hippocampus across life span.
Specific Aim 1 evaluates whether age-related declines in NMDA and AMPA receptor subunit levels in the CA1 region of the hippocampus are ameliorated by growth hormone replacement, and whether there are lower levels of hippocampal IGF-1.
Specific Aim 2 evaluates whether these changes in NMDA and AMPA receptor subunits are accompanied by a synaptic redistribution, and whether growth hormone replacement affects these synaptic alterations.
Specific Aim 3 evaluates whether low GH/IGF-1 levels are associated with functional changes in NMDA and/or AMPA receptors and with deficits in LTP expression. The proposed research will provide insight into the role of the GH/IGF-1 axis in the maintenance of neural function during normal aging and suggest strategies for the prevention or amelioration of age-related cognitive decline. As the population ages, such studies are of critical importance to this public health issue. ? ? ?
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| Molina, Doris P; Ariwodola, Olusegun J; Linville, Constance et al. (2012) Growth hormone modulates hippocampal excitatory synaptic transmission and plasticity in old rats. Neurobiol Aging 33:1938-49 |
| Adams, M M; Donohue, H S; Linville, M C et al. (2010) Age-related synapse loss in hippocampal CA3 is not reversed by caloric restriction. Neuroscience 171:373-82 |
| Adams, Michelle M; Elizabeth Forbes, M; Constance Linville, M et al. (2009) Stability of local brain levels of insulin-like growth factor-I in two well-characterized models of decreased plasma IGF-I. Growth Factors 27:181-8 |
