This competing continuation is designed to investigate the signaling mechanisms underlying hippocampal long-term potentiation (LTP) and hippocampus-dependent memory in the mouse. In particular, we will investigate the role of reactive oxygen species (ROS) in both LTP and hippocampus-dependent memory. ROS traditionally have been studied in the nervous system in the context of neurotoxicity and neurodegeneration. However, recent findings, including findings from our laboratory, indicate that ROS, especially superoxide, are critical signaling molecules that are required for both LTP and hippocampus-dependent memory. Several critical questions concerning the role of superoxide in these processes will be addressed in this proposal. First, what is the source of superoxide that is required for LTP and hippocampus-dependent memory? Our preliminary data indicate that superoxide produced by NADPH oxidase is required for LTP and hippocampus-dependent memory. This is particularly intriguing because patients with mutations in NADPH oxidase, which causes chronic granulomatous disease (CGD), have been reported to exhibit impaired cognitive ability. The second critical question we will address is: what signaling molecules are regulated by superoxide during LTP and hippocampus-dependent memory? Using a combination of biochemical, pharmacological, electrophysiological, and behavioral analyses, including studies with genetically-modified mice that model CGD, we propose to 1) test the hypothesis that activation of NADPH oxidase is necessary for LTP, 2) test the hypothesis that protein kinase C, ryanodine receptors, and NF-KB are targets of superoxide produced by NADPH oxidase during hippocampal LTP, and 3) test the hypothesis that activation of NADPH oxidase is required for hippocampus-dependent learning and memory. These studies should provide insights concerning the signaling cascades regulated by ROS during synaptic plasticity and memory function in the hippocampus. These studies also may elucidate unique signaling cascades in the hippocampus that will be critical for understanding cognitive abnormalites associated with CGD, as well as other diseases in which patients exhibit cognitive dysfunction such as Alzheimer's disease.
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