Estrogens, Ovarian Aging and Calcium Channel Modulation

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Estrogen plays a fundamental role in neuronal physiology during aging, and declining estrogens at menopause increase the incidence of stroke, cognitive impairment and inflamhiation. While estrogen therapy (ET) is beneficial in young females or following surgical menopause, ET is detrimental in older, postmenopausal females. We believe that aging and the associated dysregulation of the horriional environment controls this dichotomy by alteration of pre-and postsynaptic s exerts its biological actions through both genomic and hoh-genorriicrriechanisms. the genomid actions of estrogens have been studied for decades, but rapid, non-genomic actions only recently haye been shown to control neuronal excitability, intracellular Ca2+ signaling, and kinase/phosphatase activity through G-protein coupled receptors. The goal: of the present proposal is to use. a rat model of ovarian aging and menopause to test the non-genomic estrogenic mechanisms that control Ga2+ and synaptic function against a background of ET with individual cognitive assessrnent:Vye hypothesize that, during ovarian aging, non-genomic (membranedelimited) estrogen signaling declines at pre- and postsynaptic sites in basal forebrain (BF) cholinergic neurons and that this deficit is inequitably rescued at pre- and postsynaptic sites by ET in reproductively senescent subjects. Unequal restoration of pre- and postsynaptic rapid estrogen signaling could contribute to cognitive dysfunction. We will use functibhal (jaatch clamp recording, fluorescent imaging), behavioral (water maze), and molecular approaches (Western blotting, Rt-PCR, microRNA analyses) to test this hypothesis in female F344 rats: mature multigravid adults (MA, 5-6 mo) and reproductively senescent (RS, 14-17 mo) subjects. MA and RS will be subdivided into^ovanectomized control:(dVX) and OVX +estrogen (OVX+E) groups. BF cholinergic neurons will be targeted because they; are responsive to ET and are important in age-related cognitive decline. Our experiments will define the non-genomic actions of estrogens and how these actions are modulated by ovarian aging and ET, Identification of aberrant estrogen signaling will provide an important first step in ideritifying potential targets for future drug therapies..