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The Role of Astrocyte Activation in Anticholinesterase-Induced Synaptic Changes and Behavioral Deficits

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University of North Carolina at Pembroke Pembroke United States

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Major Goals Objective 1. A. Across subfields of paraoxon-treated hippocampal slices, we will test for colocalization of markers for reactive astrocytes increased GFAP, CSPGs and markers of neurodegeneration cytoskeletal breakdown, free radical damage, loss of synaptic proteins. Results will be compared to vehicle-treated control slice cultures. Dose-effect relationships will be made up of measures of spectrin breakdown products, synaptic markers, pyknotic nuclei, and propidium iodide uptake. B. After a defined paraoxon treatmentwashout schedule found to cause measurable but not extreme neurodegeneration, the slices will be tested for the disruption of plasticity-related myosin dynamics, i.e. myosin light chain phosphorylation pMLC triggered by brief NMDA exposure. The brief synaptic activation will consist of 30-90 s of exposure to the high concentration of 200 M NMDA. Objective 2. A. To understand the mechanistic steps involved, treatments known to inhibit astrocyte-mediated radical production and GAG levels will be tested for reducing the neurodegenerative events in paraoxon-treated slices. The agents include inhibitors of specific mitogen-activated protein kinases JNK, p38, ERK previously found to attenuate radical production and GAG expression in a model of astrocyte activation. We will also test with GAGases chondroitinase ABC, hyaluronidase, or heparinase, after which paraoxon exposure will be conducted to assess for whether reduced levels of neurodegeneration was produced. B. Treatments known to inhibit astrocyte-mediated radical production and GAG levels will be tested for reducing the vulnerability produced after paraoxon exposure. The latter is tested since prior anticholinesterase exposure leads to enhanced vulnerability to excitotoxic insults e.g. stroke, TBI. Objective 3. A. Observations will be made with in vivo models of rats and mice injected with a range of paraoxon dosages.

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Technical Report,21 Aug 2015,20 Aug 2019



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Approved For Public Release;

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