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Dissertation
Characterizing enhanced metabotropic glutamate receptor mediated long-term depression in the Fmr1 KO mice and its abrogation by pharmacologic treatments
Doctor of Philosophy (Ph.D.), Drexel University
Oct 2007
DOI:
https://doi.org/10.17918/00000613
Abstract
Fragile X syndrome is the most prevalent heritable cause of mental retardation, affecting 1 in 3,600 births. The disease involves a single gene, FMR1, that is transcriptionally silenced as a result of hypermethylation of a CGG trinucleotide expansion in the promotor region. The consequent loss of the gene product, FMRP, is responsible for a constellation of symptoms, of which the overriding clinical manifestation is mild to severe mental retardation. Although the function of FMRP remains to be fully understood, it is known that FMRP binds and regulates the translation of mRNAs. A Drosophila model for Fragile X, based on the loss of dfmr1 expression, exhibits several phenotypes that bear similarity to Fragile X-related symptoms including impairments in social interaction and cognition. Previously, I demonstrated that treatment with metabotropic glutamate receptor (mGluR) antagonists, a PDE-4 inhibitor or lithium can rescue social interaction and cognitive deficits. The goal of this thesis was to translate my findings in the dfmr1 mutants to the Fmr1 KO mice, specifically to determine the efficacy of the aforementioned pharmacologic strategies in ameliorating a endophenotype associated with cognition. The most robust endophenotype described to date in the Fmr1 KO is exaggerated metabotropic glutamate receptor (mGluR)-dependent long-term depression in the CA1 region of the hippocampus. Herein, I demonstrate that this endophenotype of enhanced DHPG-induced mGluR-LTD persists through adulthood in the Fmr1 KO mice, and that it is rescued by similar pharmacologic strategies employed in the Fragile X flies, specifically a mGluR antagonist, a PDE-4 inhibitor and lithium. Additionally, I have been able to target a signaling pathway at three distinct points and demonstrate restoration of the endophenotype of enhanced mGluR-LTD, which is very encouraging given that pharmacologic management of many diseases in humans requires combinatorial therapy and multiple therapeutic targets for successful treatment to be achieved.
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Details
- Title
- Characterizing enhanced metabotropic glutamate receptor mediated long-term depression in the Fmr1 KO mice and its abrogation by pharmacologic treatments
- Creators
- Catherine Helen Choi
- Contributors
- Melanie Tallent (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xviii, 199 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991014970334904721