This application is designed to investigate the biochemical signaling underlying hippocampal long-term potentiation (LTP), a form of synpatic plasticity widely thought to be a cellular substrate for mammalian learning and memory processes. Protein kinases are one class of signaling enzymes that are activated during LTP and are thought to be necessary for both LTP and learning and memory. One example is protein kinase C (PKC), which has been shown to be necessary for and activated during LTP. Oxygen free radicals are thought to contribute to neurodegeneration in diseases such as amytrophic lateral sclerosis and Alzheimer's disease. Historically, these reactive oxygen species (ROS) have been thought to be toxic agents that disrupt normal cellular, including neuronal function. However, in the past decade, a number of studies have suggested that some ROS may be involved in normal cellular, including neuronal, function as cellular messenger molecules. Recent studies have indicated that the ROS superoxide is necessary for LTP. The molecular targets for the action of this and/or other ROS are largely unknown. In addition, the enzymatic mechanism by which superoxide is produced after LTP-inducing stimulation also is unknown. We propose to investigate the interactions of superoxide with PKC during induction of LTP. Using a combination of biochemical, immunocytochemical, pharmacological, and electrophysiological techniques, we propose to 1) test the hypothesis that LTP-inducing stimulation results in the production of oxidatively-activated PKC, 2) test the hypothesis that superoxide potentiates synaptic transmission in area CA1 in a PKC-dependent manner, 3) test the hypothesis that superoxide can be generated by activation of a functional NADPH oxidase in the hippocampus and that this activation occurs in response to LTP-inducing stimulation, and 4) test the hypothesis that NADPH oxidase is necessary for LTP in area CA1. By combining a number of experimental approaches, we will be able to thoroughly address these questions. These studies should enhance our understanding of how long-term alterations in neuronal function are regulated by ROS-induced activation of signal transduction cascades. These studies also should provide insight on how abberations in naturally occuring production of ROS in neurons could- result in neurodegeneration and brain dysfunction manifested in diseases such as amytrophic lateral sclerosis and Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS034007-06
Application #
6130141
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Heemskerk, Jill E
Project Start
1995-05-01
Project End
2005-03-31
Budget Start
2000-04-05
Budget End
2001-03-31
Support Year
6
Fiscal Year
2000
Total Cost
$266,716
Indirect Cost
Name
University of Pittsburgh
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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