Role of GPR30 in Estrogen-Mediated Effects on Cholinergic Function and Cognition

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Animal studies show that estrogens can significantly enhance learning and memory; however, the mechanisms that underlie these effects are very unclear. Studies suggest that neurons that project to the hippocampus and frontal cortex, and that use acetylcholine as their neurotransmitter, play an important role in these effects. The purpose of this project is to study whether a novel estrogen receptor protein, GPR30, plays an important role in mediating effects on the function of the cholinergic neurons as well as on learning and memory. Studies will be performed in rats that have had their ovaries removed. Histochemistry, behavioral pharmacology, and in vivo microdialysis will be used to evaluate the effects of drugs that act on the GPR30 receptor. It is predicted that selective activation of the GPR30 receptor will significantly enhance the function of the cholinergic neurons of interest, as well as cognitive performance. In addition, it is predicted that drugs which block activation of the GPR30 receptors, or that destroy the cholinergic neurons of interest, will block the effects of estradiol as well as effects associated specifically with GPR30 activation. This would demonstrate that GPR30, which is expressed by the cholinergic neurons, plays an important role in mediating the effects of estradiol. Cell culture studies also will be used to evaluate effects on signaling pathways within the cholinergic neurons. These studies will provide much new and valuable mechanistic information about the role of GPR30 in mediating estrogen effects on the cholinergic neurons and on cognitive performance. This information will add significantly to our understanding of how loss of ovarian function as well as estrogen replacement influences cognition. Doctoral and undergraduate students will benefit by receiving training in methods of behavioral pharmacology, histochemistry, and in vivo microdialysis.