In Project 3, a neurotoxicological and behavioral studies are proposed to test the hypothesis that sensitivity to the effects results from suppression of N-methyl-D-aspartate (NMDA) receptor function, referred to as NRHYPO, is increased in mice containing transgenes pertaining to the expression of human apolipoprotein E (apoE) and beta amyloid precursor protein (APP). This hypothesis was derived from our NRHYPO model of Alzheimer's disease (AD) which was developed on the basis of experiments showing that low to moderate doses of NMDA antagonists induce reversible neuronal injury in the posterior cingulate/retrosplenial cortex (PC/RSC) and that high doses produce neurodegeneration in the PC/RSC and other corticolimbic areas in rodents. There is substantial evidence in several animal species that NRHYPO naturally occurs with advancing age. We have proposed that certain adjunctive risk factors, such as amyloidosis and/or certain genetic predispositions like the presence of apoE4 alleles, may be present in the AD brain and promote the NRHYPO state and increase the likelihood that widespread neurodegeneration will occur. In dose-response neurotoxicological studies, apoE and APP transgenes (APP/apoE), will be administered moderate doses of the NDA antagonist MK-801 to determine whether their sensitivity to the reversible neuronal injury induced by the drug in the PC/RSC is increased. In other dose-response experiments, the apoE, APP, and APP/apoE TG mice will receive high doses of MK-801 to determine if their sensitivity to drug-induced neurodegeneration in the PC/RSC and other corticolimbic regions is enhanced. We will also evaluate whether our TG mice show an increased sensitivity to the transient impairment in spatial learning/memory induced by low doses of MK-801 or the long-term deficits induced by high, neurodegenerative learning/memory induced by low doses of MK-801 or the long-term deficits induced by high neuro-degenerative doses of MK-801. The proposed studies will provide information on whether adding NRHypo to apoE, APP, or APP/apoE models provide more useful models of AD than any of the models by themselves.
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