Aging and diseases involving dementia such as Alzheimer's disease are characterized by deficits in memory function. The role of calcium (Ca2+) regulation has been the focus of research on age-related neurodegenerative mechanisms and development of potential treatments for dementia in humans. However, the challenge remains to determine the key elements that link altered Ca2+ homeostasis with cellular changes and memory impairment. Over the past two decades much of the research on neural mechanisms of memory has been directed at the examination of synaptic plasticity. The level of cytosolic free Ca2+ occupies a pivotal position in regulating synaptic plasticity thought to underlie memory. The direction of synaptic modification is believed by many to be determined by the level of intracellular Ca2+. Low levels of calcium influx during low levels of synaptic activity lead to activation of calcium influx increases and Ca2+-dependent kinases are activated resulting in long-term synaptic potentiation (LTP). Previous research has demonstrated that susceptibility to synaptic plasticity is altered during aging. The results suggest the hypothesis that mechanisms regulating synaptic modification are involved in altered synaptic function and memory deficits. Studies are proposed to test the hypothesis that age-related changes in synaptic modification are due to altered synaptic modification thresholds. A model is proposed which links VDCC function with plasticity thresholds. Finally, studies are designed to test the hypothesis that the increased susceptibility to synaptic depression underlies the decrease in CA3-CA1 synaptic strength of aged animals through increased activation of serine/threonine protein phosphatases. The results of these experiments will add significantly to our knowledge of mechanisms for regulation of synaptic function across the life span and provide a basis for understanding the role of synaptic plasticity in cognitive function.
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