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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG014979-01
Application #
2441588
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1997-12-01
Project End
1998-09-30
Budget Start
1997-12-01
Budget End
1998-09-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Virginia
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Kumar, Ashok; Rani, Asha; Scheinert, Rachel B et al. (2018) Nonsteroidal anti-inflammatory drug, indomethacin improves spatial memory and NMDA receptor function in aged animals. Neurobiol Aging 70:184-193
Kumar, Ashok; Foster, Thomas C (2018) Alteration in NMDA Receptor Mediated Glutamatergic Neurotransmission in the Hippocampus During Senescence. Neurochem Res :
Kumar, Ashok; Bean, Linda A; Rani, Asha et al. (2015) Contribution of estrogen receptor subtypes, ER?, ER?, and GPER1 in rapid estradiol-mediated enhancement of hippocampal synaptic transmission in mice. Hippocampus 25:1556-66
Scheinert, Rachel B; Asokan, Aditya; Rani, Asha et al. (2015) Some hormone, cytokine and chemokine levels that change across lifespan vary by cognitive status in male Fischer 344 rats. Brain Behav Immun 49:216-32
Speisman, Rachel B; Kumar, Ashok; Rani, Asha et al. (2013) Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats. Brain Behav Immun 28:25-43
Speisman, Rachel B; Kumar, Ashok; Rani, Asha et al. (2013) Environmental enrichment restores neurogenesis and rapid acquisition in aged rats. Neurobiol Aging 34:263-74
Boye, Sanford L; Peshenko, Igor V; Huang, Wei Chieh et al. (2013) AAV-mediated gene therapy in the guanylate cyclase (RetGC1/RetGC2) double knockout mouse model of Leber congenital amaurosis. Hum Gene Ther 24:189-202
Brim, B L; Haskell, R; Awedikian, R et al. (2013) Memory in aged mice is rescued by enhanced expression of the GluN2B subunit of the NMDA receptor. Behav Brain Res 238:211-26
Han, Xiaoxia; Aenlle, Kristina K; Bean, Linda A et al. (2013) Role of estrogen receptor ýý and ýý in preserving hippocampal function during aging. J Neurosci 33:2671-83
Guidi, Michael; Foster, Thomas C (2012) Behavioral model for assessing cognitive decline. Methods Mol Biol 829:145-53

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