The primary cognitive deficit associated with aging and Alzheimer's disease is impairment of memory processes that require proper hippocampal function. Regulation of Ca2+ is thought to play a role in age-related neurodegeneration and the synaptic plasticity that underlies memory. However, the key elements that link Ca2+ homeostasis with memory or memory impairment remain to be determined. Our work, supported by the preceding award, provides evidence that a decrease in neural transmission through the hippocampus, which is characteristic of age-related memory impairments, results from a shift in susceptibility to induction of synaptic plasticity favoring synaptic depression. The shift in synaptic plasticity is linked to changes in Ca2+ sources with increased contributions from voltage-dependent L-channels and intracellular Ca2+ stores and decreased contributions from NMDA receptors. The Ca2+ dysregulation alters subsequent Ca2+-dependent process, particularly the Ca2+-dependent afterhyperpolarization (AHP), and the activity of the Ca2+-dependent phosphatase, calcineurin, and ultimately gene transcription. In turn, the amplitude of the AHP and level of calcineurin activity regulate synaptic modifiability and are correlated with memory function. Together, these elements provide physiological and biochemical models which link Ca2+ dysregulation to senescent physiology and biochemistry thought to mediate memory. Currently there is a gap in our knowledge concerning the process that leads to Ca2+ dysregulation. Research suggests that oxidative stress can impair Ca2+ homeostasis and synaptic plasticity in a manner similar to that observed during aging. Thus, the current proposal examines oxidative stress as a potential mechanism and target for treatment of Ca2+ dysregulation.
Specific aim 1 will employ conditioning treatments which have been shown to reduce oxidative stress and/or improved memory. We will determine if improved memory is associated with changes in Ca2+- dependent processes as predicted by our model.
Specific aim 2 will apply pharmacological treatments and gene manipulations to reduce oxidative stress to determine if these treatments modify markers of brain aging and improve memory. Specifc aim 3 will addresses the issue of how oxidative stress contributes to calcium dysregulation during aging in the hippocampus by examining the influence of redox state on Ca2+ dependent processes. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG014979-11
Application #
7429744
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Wise, Bradley C
Project Start
1997-12-01
Project End
2012-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
11
Fiscal Year
2008
Total Cost
$264,887
Indirect Cost
Name
University of Florida
Department
Neurosciences
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Kumar, Ashok; Foster, Thomas C (2018) Alteration in NMDA Receptor Mediated Glutamatergic Neurotransmission in the Hippocampus During Senescence. Neurochem Res :
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; 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
Foster, Thomas C (2012) Dissecting the age-related decline on spatial learning and memory tasks in rodent models: N-methyl-D-aspartate receptors and voltage-dependent Ca2+ channels in senescent synaptic plasticity. Prog Neurobiol 96:283-303

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