This is the resubmission of a renewal application for a longstanding project on dysregulation of calcium (Ca2+)-related processes in hippocampal neurons during aging and the consequences for altered neuronal function/vulnerability. The project initially derived from the finding that the Ca2+-dependent slow afterhyperpolarization (sAHP), that follows a burst of action potentials in hippocampal pyramidal neurons, is larger in aged than in young-adult animals. Importantly, larger sAHPs are correlated with reduced neuronal excitability and impaired learning and memory. Conversely, smaller sAHPs are found in animals that learn a task. Since then, we and others have determined that Ca2+ action potentials, Ca2+ transients and L-type Ca2+ currents also are increased in aged neurons. These results led to a Ca2+ dysregulation hypothesis of brain aging, in which increased activity of L-channels plays a key initiating role and the resulting larger sAHP reduces neuronal excitability. It also has become apparent that enhanced Ca2+-induced Ca2+ release (CICR) from ryanodine receptors (RyRs) modulates the magnitude of aging-related Ca2+ transients and sAHPs in pyramidal neurons. The major objective of this project is to fundamentally advance our understanding of the underlying molecular mechanisms of Ca2+ dysregulation that lead to unhealthy brain aging. Based on our new intriguing results, we have formulated a novel working hypothesis of age-related Ca2+ dysregulation that suggests that downregulation of immunophilins, particularly FK-506 binding protein 1b and/or 1a (FKBP1b/1a), leads to a cascade of RyR destabilization, greater CICR and larger sAHPs. The resulting effect is impaired neuronal excitability and behavioral plasticity. These studies will manipulate hippocampal expression/function of FKBP1b/1a and other proteins in the FKBP- Ca2+ regulatory pathway in vivo using microinjection of viral vectors. Multiple outcomes will be assessed in the same animals using a multidisciplinary approach comprising extensive behavioral testing, state-of-the-art intracellular electrophysiology with concomitant Ca2+ imaging, immunohistochemistry, and gene microarray analysis. These studies should substantially elucidate aging changes that depend on Ca2+ dysregulation and should clearly test the role of FKBPs in Ca2+ dysregulation and hippocampal function during aging. Chronic intervention studies are proposed that could have direct translational relevance and lead directly to novel preventative and therapeutic treatments against aging-related decline of brain function. Given the dramatic increase in the aging population, it is becoming increasingly important to identify and develop such therapies to maintain cognitive function in the elderly.

Public Health Relevance

The aging population of the United States is projected to increase at a dramatic rate with numbers that will undoubtedly impact our healthcare system (20% of the population will be >65 years of age by the year 2030). Cognitive decline frequently accompanies aging and depending on the severity, can significantly affect quality of life. Our results indicate that a specific pathway (FKBP-Ca2+) that plays a major role in cardiac failure may also play a critical role in brain aging and cognitive decline;thus the goal of this project is to use gene therapy techniques to determine whether such interventions can prevent or slow the onset of age-related brain decline. The outcomes may have substantial therapeutic implications.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG004542-23
Application #
8235801
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Wise, Bradley C
Project Start
1998-01-01
Project End
2016-02-29
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
23
Fiscal Year
2012
Total Cost
$390,589
Indirect Cost
$127,566
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Blalock, Eric M; Buechel, Heather M; Popovic, Jelena et al. (2011) Microarray analyses of laser-captured hippocampus reveal distinct gray and white matter signatures associated with incipient Alzheimer's disease. J Chem Neuroanat 42:118-26
Gant, John C; Chen, Kuey-Chu; Norris, Christopher M et al. (2011) Disrupting function of FK506-binding protein 1b/12.6 induces the Ca²+-dysregulation aging phenotype in hippocampal neurons. J Neurosci 31:1693-703
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Thibault, Olivier; Gant, John C; Landfield, Philip W (2007) Expansion of the calcium hypothesis of brain aging and Alzheimer's disease: minding the store. Aging Cell 6:307-17
Gant, John C; Sama, Michelle M; Landfield, Philip W et al. (2006) Early and simultaneous emergence of multiple hippocampal biomarkers of aging is mediated by Ca2+-induced Ca2+ release. J Neurosci 26:3482-90
Norris, C M; Blalock, E M; Thibault, O et al. (2006) Electrophysiological mechanisms of delayed excitotoxicity: positive feedback loop between NMDA receptor current and depolarization-mediated glutamate release. J Neurophysiol 96:2488-500

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