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Permanent link (DOI): https://doi.org/10.7939/R3D21RV6V

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Understanding the Molecular Basis of Memory Defects in Fragile X Syndrome Open Access

Descriptions

Other title
Subject/Keyword
Fragile X Syndrome
Neuroscience
Drosophila
Intellectual Disability
Learning and Memory
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Chambers, Daniel B
Supervisor and department
Bolduc, Francois (Pediatrics)
Kerr, Bradley (Anesthesiology and Pain Medicine)
Examining committee member and department
Hughes, Sarah (Medical Genetics)
Power, Christopher (Medicine)
Dickson, Clayton (Psychology)
Department
Centre for Neuroscience
Specialization

Date accepted
2014-06-27T11:38:15Z
Graduation date
2014-11
Degree
Master of Science
Degree level
Master's
Abstract
Fragile X Syndrome (FXS) is the most common genetic cause of Intellectual Disability, affecting 1 in 4000 boys and 1 in 6000 girls. Work in our lab using Drosophila melanogaster and since replicated in the mouse model has shown that excess protein synthesis is a major mechanism connecting the observed learning and memory problems and the mutation in the fragile x gene. My masters thesis project aims at understanding further the molecular mechanisms leading to dysregulation in protein synthesis in Fragile X. Previous research has found a major protein synthesis regulation pathway, the AKT-mTOR pathway to be disrupted in Fragile X mice (Sharma et al., 2010). I initially carried out an analysis of potential target proteins within the AKT-mTOR axis of the Insulin Receptor pathway in a Drosophila melanogaster (fruit fly) model of Fragile X syndrome. This identified multiple targets that are dysregulated in Fragile X. We show that decreasing Insulin signaling in neurons throughout the brain results in impairments of both learning and protein synthesis dependent memory specifically. The final phase of this project was to identify treatment methods for Fragile X syndrome. We selected drugs targeting key candidate proteins misregulated in Fragile X mutant flies. Acute administration of Metformin, a hypoglycemiant, and Rolipram, an inhibitor of phosphodiesterase, led to significant rescuing of the learning and memory defects seen in Fragile X. Taken together the data may offer new insights into the molecular mechanisms underlying the learning and memory defects seen in Fragile X syndrome and identify potential treatment methods to improve learning and memory defects.
Language
English
DOI
doi:10.7939/R3D21RV6V
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
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