The major objective of this project is to understand the role of ionotropic glutamate receptors in the cognitive decrements often associated with aging.
The first aim i ncludes a determination of the relationship between phosphorylation of NMDA and AMPA receptor subunits and cognitive performance in young and aged rats. Additionally, the level of neurotransmitter release stimulated by NMDA receptors will be examined in young and aged, behaviorally-characterized rats.
The second aim characterized the role of phosphorylation of NMDA and AMPA subunits in a specific learning paradigm by using a behavioral/electrophysiological procedure developed by Dr. Eichenbaum which produces learning-related alterations in synaptic efficacy in specific hippocampal pathways.
This aim i s based on the observation that protein phosphorylation plays an important in LTP and that phosphorylation of specific subunits of ionotropic glutamate receptors subunits appears to be a major mechanism for regulating receptor function. Thus, if phosphorylation is induced by the learning paradigm in young rats, this phenomenon will be examined in aged, behaviorally-characterized rats.
The third aim of this project, a collaboration with Drs. Gallagher and McKinney, is to study glucocorticoid receptors and associated transcription factors and their relationship to hippocampal aging. A great deal of evidence implicates dysregulation of glucocorticoids in the negative consequences of aging, particularly in the hippocampus. Experiments are designed to determine if glucocorticoid receptors or APl, which can be associated, are altered in aging and if this alteration is related to cognitive decline. In these studies the parallel to the human condition is clear in that, like the rats used in the experiments, some humans age with little or no loss of cognitive abilities while others tend to have a serious decline in cognition associated with aging. A better understanding of the biochemical events responsible for this difference may lead to novel approaches to alter the age-related cognitive decline.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG009973-10
Application #
6398180
Study Section
Project Start
2000-09-15
Project End
2001-11-30
Budget Start
Budget End
Support Year
10
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Haberman, Rebecca P; Koh, Ming Teng; Gallagher, Michela (2017) Heightened cortical excitability in aged rodents with memory impairment. Neurobiol Aging 54:144-151
Haberman, Rebecca P; Branch, Audrey; Gallagher, Michela (2017) Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease. Neurotherapeutics 14:662-676
Posada-Duque, Rafael Andrés; Ramirez, Omar; Härtel, Steffen et al. (2017) CDK5 downregulation enhances synaptic plasticity. Cell Mol Life Sci 74:153-172
Gu, Yu; Tran, Trinh; Murase, Sachiko et al. (2016) Neuregulin-Dependent Regulation of Fast-Spiking Interneuron Excitability Controls the Timing of the Critical Period. J Neurosci 36:10285-10295
Wang, Hui; Ardiles, Alvaro O; Yang, Sunggu et al. (2016) Metabotropic Glutamate Receptors Induce a Form of LTP Controlled by Translation and Arc Signaling in the Hippocampus. J Neurosci 36:1723-9
Robitsek, Jonathan; Ratner, Marcia H; Stewart, Tara et al. (2015) Combined administration of levetiracetam and valproic acid attenuates age-related hyperactivity of CA3 place cells, reduces place field area, and increases spatial information content in aged rat hippocampus. Hippocampus 25:1541-55
Tomás Pereira, Inês; Gallagher, Michela; Rapp, Peter R (2015) Head west or left, east or right: interactions between memory systems in neurocognitive aging. Neurobiol Aging 36:3067-3078
Gallagher, Michela; Burwell, Rebecca; Burchinal, Margaret (2015) Severity of spatial learning impairment in aging: Development of a learning index for performance in the Morris water maze. Behav Neurosci 129:540-8
Mayse, Jeffrey D; Nelson, Geoffrey M; Avila, Irene et al. (2015) Basal forebrain neuronal inhibition enables rapid behavioral stopping. Nat Neurosci 18:1501-8
Castellano, James F; Fletcher, Bonnie R; Patzke, Holger et al. (2014) Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging. Hippocampus 24:1006-16

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