Hammond, Rebecca
(2012)
THE ROLE OF GPR30 IN MEDIATING ESTROGEN EFFECTS ON NEURONS AND COGNITIVE PERFORMANCE.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Basic and clinical research suggests the loss of estradiol following menopause may contribute to accelerated brain aging and the increased risk of age-related cognitive decline and dementia. Novel estrogenic compounds may confer positive cognitive effects without the added risk of side effects associated with current agents. G-1 is a recently developed agonist for the novel transmembrane estrogen receptor (ER) GPR30. Activation of the GPR30 pathway is independent of either the classical ER α or β pathways, raising the possibility of using G-1 as a novel estrogenic agent while avoiding the risks associated with other estrogenic compounds. Previous work in our laboratory has shown that estradiol enhances cognitive performance via effects on basal forebrain cholinergic neurons. We hypothesize the effects of estradiol on cholinergic function and cognitive performance are mediated by GPR30. If correct, then selective GPR30 agonists may provide useful alternatives to current estrogenic therapies. To test this hypothesis the first goal was to characterize GPR30 expression in the rat forebrain, focusing on co-expression by cholinergic neurons. A RT-PCR assay was developed to quantify GPR30 mRNA in specific brain regions. GPR30 protein and mRNA expression were found in regions of the brain important for spatial learning and memory. Moreover, GPR30 protein appears to be expressed by the vast majority of cholinergic neurons. The second goal was to examine the effects of GPR30 activation on cholinergic neurons. In vivo microdialysis and HPLC analysis of acetylcholine levels in dialysates were used to compare effects on acetylcholine release. Administration of a GPR30 agonist or estradiol (E2) to ovariectomized (OVX) rats produced a 3-fold increase in potassium-stimulated acetylcholine release in the hippocampus relative to vehicle-treated controls. The third goal was to test the ability of GPR30 agonists and antagonists to enhance or impair cognitive performance in rats. GPR30 agonism enhanced the rate of acquisition on a delayed matching-to-position (DMP) T-maze task in OVX rats similar to estradiol while GPR30 antagonism dose-dependently impaired performance in gonadally intact and OVX+E2 rodents. Hence, GPR30 appears to play an important role in mediating direct effects of estradiol on basal forebrain cholinergic neurons, with corresponding effects on cognitive performance.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
24 July 2012 |
| Date Type: |
Publication |
| Defense Date: |
30 May 2012 |
| Approval Date: |
24 July 2012 |
| Submission Date: |
11 July 2012 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
92 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
This thesis describes studies done to characterize a novel estrogen receptor named GPR30. It examines GPR30 expression in the rat brain, looks at how GPR30 activation affects cholinergic neurons, and tests whether GPR30 activation and inhibition enhances or impairs spatial learning in rats. |
| Date Deposited: |
24 Jul 2012 13:11 |
| Last Modified: |
15 Nov 2016 14:00 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/12866 |
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