Abstract

This application is to continue basic research into membrane and synaptic mechanisms of mammalian brain aging, using a specific-pathogen-free aged rat model. Studies are conducted primarily In hippocampal slices (with some work In anesthetized animals), using a combination of voltage-damp procedures, conventional Intracellular recording, receptor analyses and quantative electron microscopy. Research during the preceding phase revealed that aged rat hippocampal neurons exhibit consistent Increases of voltage-sensitive calcium (Ca) currents, which apparently Is the cause of Impaired synaptic potentiation In these animals. Synaptic vesicle analyses showed that vesicle depletion is not the cause of Increased synaptic depression with aging. In addition, corticosteroids (CORT) were found to increase apparent Ca influx, and to do so more with aging. Several aging changes in CORT receptors were found, which could account for the greater Impact of CORT with aging. In the next phase, it is proposed to a) study the causes and nature of aging-related Increases in Ca Influx In much greater detail, using voltage- and patch-damping approaches In the slice; b) assess the role of phosphorylation In Ca channel modulation and in Ca current changes with aging; c) analyze mechanisms of aging changes in the corticosteroid modulation of Ca Influx; d) study possible changes in receptor-gated Ca channels (NMDA) with aging; and e) assess the role of these membrane current changes In modifying synaptic potentiation and depression, using Intracellular recording and quantitative E.M. analyses of vesicle patterns. These studies could clarify the basis of brain cell decline with aging and/or Alzheimer's disease, since both glucocorticoids and altered Ca homeostasis are suspected of roles in aging-dependent neuronal degeneration.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG004542-07
Application #
3115187
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1991-05-01
Project End
1996-04-30
Budget Start
1991-05-01
Budget End
1992-04-30
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
University of Kentucky
Department
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506

  Publications

Latimer, Caitlin S; Brewer, Lawrence D; Searcy, James L et al. (2014) Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats. Proc Natl Acad Sci U S A 111:E4359-66
Gant, J C; Blalock, E M; Chen, K-C et al. (2014) FK506-binding protein 1b/12.6: a key to aging-related hippocampal Ca2+ dysregulation? Eur J Pharmacol 739:74-82
Thibault, Olivier; Pancani, Tristano; Landfield, Philip W et al. (2012) Reduction in neuronal L-type calcium channel activity in a double knock-in mouse model of Alzheimer's disease. Biochim Biophys Acta 1822:546-9
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
Norris, Christopher M; Blalock, Eric M; Chen, Kuey-Chu et al. (2010) Hippocampal 'zipper' slice studies reveal a necessary role for calcineurin in the increased activity of L-type Ca(2+) channels with aging. Neurobiol Aging 31:328-38
Gant, John C; Thibault, Olivier (2009) Action potential throughput in aged rat hippocampal neurons: regulation by selective forms of hyperpolarization. Neurobiol Aging 30:2053-64
Rowe, Wayne B; Blalock, Eric M; Chen, Kuey-Chu et al. (2007) Hippocampal expression analyses reveal selective association of immediate-early, neuroenergetic, and myelinogenic pathways with cognitive impairment in aged rats. J Neurosci 27:3098-110
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
Brewer, Lawrence D; Porter, Nada M; Kerr, D Steven et al. (2006) Chronic 1alpha,25-(OH)2 vitamin D3 treatment reduces Ca2+ -mediated hippocampal biomarkers of aging. Cell Calcium 40:277-86

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