This project addresses steroidal influences of synaptic remodeling in the rodent brain in vivo and in vitro with cell culture models, with a focus on astrocyte genes that are regulated by estradiol (E2) and corticosterone. Little is known about how steroids modulate gene expression in relation to spontaneous and injury-induced synaptic remodelling. This information is crucial to optimizing estrogen replacement therapy (ERT) in the prevention and treatment of Alzheimer disease (AD). We emphasize the regulation of GFAP and other mRNAs in the hippocampus, a brain region that is well studied for synaptic plasticity in association with learning and memory and in response to lesioning, but hat also shows a physiological synaptic remodelling during the rat estrus cycle. The regulation of GFAP receives most attention, because of its sensitivity to sex steroids, glucocorticoids, and lesions, and because of prominent age-related increases in GFAP mRNA and protein. Other responses to lesions and steroids include genes expressed in astrocytes that mediate lipoprotein trafficking and genes expressed in neurons that encode proteins of the cytoskeleton and growth cones. As an efficient in vitro model for steroid-lesion interactions, we are studying """"""""wounding-in-a-dish"""""""" with montypic cultures of primary astrocytes, with and without co-cultured neurons. In vivo studies with female rats examine astrocyte- and neuron-expressed genes in response to E2 treatment, perforant path lesions, and E- lesion interactions. Aging rats will be examined for select responses. To probe the basis for the protective effects of ERT in AD, we will use these models to compare the effects of Premarin and its equine estrogen constituents with those of E2.
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