This project developed out of studies on calcium (Ca2+) regulation in age-related neurodegeneration and examination of Ca2+ dependent synaptic plasticity as a neural mechanism for memory. Previous electrophysiological studies in this project found an age-related shift in the balance of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), favoring LTD. The shift in the LTD/LTP balance was associated with Ca2+-dysregulation involving L-type Ca2+ channels and the activity of protein phosphatases and kinases involved in synaptic plasticity. From this work we have proposed the hypothesis that a Ca2+ dependent enhancement of LTD relative to LTP is a major factor in synaptic and cognitive impairment with age. Here we will focus on two main goals: 1) to test the hypothesized link between the LTD/LTP shift and cognitive decline in aging, and 2) to unravel the cellular mechanistic pathways through which age-related altered Ca2+ regulation is linked to the LTD/LTP shift.
Specific aims are designed to determine if the age-related shift in LTD/LTP is associated with cognitive decline and determine whether procedures to counteract shift in LTD/LIP also counteracts the memory impairment in aged animals.
Other aims will determine whether intracellular Ca2+ stores contribute to altered synaptic plasticity during aging, and identify intermediate linking steps between Ca2+ dysregulation and altered synaptic function (e.g. calcineurin). We believe that the results of our 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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