This is a proposal for a competitive continuation of a project on basic membrane and synaptic mechanisms of brain aging that has been ongoing for over 15 years. The past periods in this project have found two main electrophysiological alterations in rat hippocampal CAl neurons with aging: 1) impaired synaptic frequency potentiation (facilitation); and 2) an increase in voltage-gated Ca2+ influx. These results and others have contributed to the general Ca2+ hypothesis of brain aging and dementia. In the most recent period, the single channel patch clamp configuration was adapted for brain aging studies and identified an increase in the membrane density of available L-type Ca2+ channels as a potential molecular basis for the changes with aging seen at the cellular level. Here, the specific hypothesis that the increase in L-type Ca2+ channels is a key mechanism in both impaired function (synaptic potentiation or spike generation) and neuronal vulnerability to death of aged mammalian neurons will be tested. Studies will be conducted in rat hippocampal slices and long-term hippocampal cultures in which L-type Ca2+ channels are enriched. Effects of repetitive synaptic activation on the magnitude and topography of Ca2+ transients in hippocampal slice neurons of adult and aged rats will be studied, using a rapid UV-compatible confocal laser scanning microscope for Ca2+ imaging simultaneously with intracellular electrophysiological recording. Multiple specific channel blockers and kinase modulators will be used to define critical Ca2+ entry pathways. These studies will determine whether postsynaptic Ca2+ transients, particularly through L-channels, can modulate neuronal short-term synaptic plasticity and contribute to changes in aged brain neurons. In parallel studies of cell cultures, the role of time-dependent ion channel changes in cell death will be tested, by investigating differences in vulnerability to excitotoxicity in cells with different complements of L-type channels. Single channel recording, Ca2+ imaging, pharmacologic blockade and kinase modulation will be used to define Ca2+ sources critical for necrosis and apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37AG004542-12
Application #
2695689
Study Section
Cognitive Functional Neuroscience Review Committee (CFN)
Project Start
1998-01-01
Project End
2002-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
12
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Gant, John C; Blalock, Eric M; Chen, Kuey-Chu et al. (2018) FK506-Binding Protein 12.6/1b, a Negative Regulator of [Ca2+], Rescues Memory and Restores Genomic Regulation in the Hippocampus of Aging Rats. J Neurosci 38:1030-1041
Gant, John C; Kadish, Inga; Chen, Kuey-Chu et al. (2018) Aging-Related Calcium Dysregulation in Rat Entorhinal Neurons Homologous with the Human Entorhinal Neurons in which Alzheimer's Disease Neurofibrillary Tangles First Appear. J Alzheimers Dis 66:1371-1378
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Alzheimer's Association Calcium Hypothesis Workgroup (2017) Calcium Hypothesis of Alzheimer's disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis. Alzheimers Dement 13:178-182.e17
Gant, John C; Chen, Kuey-Chu; Kadish, Inga et al. (2015) Reversal of Aging-Related Neuronal Ca2+ Dysregulation and Cognitive Impairment by Delivery of a Transgene Encoding FK506-Binding Protein 12.6/1b to the Hippocampus. J Neurosci 35:10878-87
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; Anderson, Katie L; DeMoll, Chris et al. (2013) Hippocampal calcium dysregulation at the nexus of diabetes and brain aging. Eur J Pharmacol 719:34-43
Pancani, Tristano; Anderson, Katie L; Brewer, Lawrence D et al. (2013) Effect of high-fat diet on metabolic indices, cognition, and neuronal physiology in aging F344 rats. Neurobiol Aging 34:1977-87
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

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