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Understanding the Molecular Basis of Memory Defects in Fragile X Syndrome

  • Author / Creator
    Chambers, Daniel B
  • 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.

  • Subjects / Keywords
  • Graduation date
    2014-11
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/R3D21RV6V
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. 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.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Master's
  • Department
    • Centre for Neuroscience
  • Supervisor / co-supervisor and their department(s)
    • Bolduc, Francois (Pediatrics)
    • Kerr, Bradley (Anesthesiology and Pain Medicine)
  • Examining committee members and their departments
    • Dickson, Clayton (Psychology)
    • Power, Christopher (Medicine)
    • Hughes, Sarah (Medical Genetics)