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Cyclic Adenosine Monophosphate (cAMP) and Fragile X Mental Retardation Protein (FMRP) Mediate Avoidance Behaviour in Drosophila Open Access

Descriptions

Other title
Subject/Keyword
sensory processing
Fragile X Syndrome
cyclic adenosine monophosphate
Armadillo
long-term memory reversal
learning reversal
avoidance
Fragile X mental retardation protein
Drosophila
Beta-catenin
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Androschuk, Alaura MA
Supervisor and department
Bolduc, Francois (Paediatrics)
Examining committee member and department
Hughes, Sarah (Medical Genetics)
Yager, Jerome (Paediatrics)
Bourque, Stephane (Anesthesiology & Pain Medicine)
Baksh, Shairaz (Paediatrics)
Department
Medical Sciences-Paediatrics
Specialization

Date accepted
2016-07-22T13:45:44Z
Graduation date
2016-06:Fall 2016
Degree
Master of Science
Degree level
Master's
Abstract
Fragile X Syndrome (FXS) is neurodevelopmental disorder caused by a trinucleotide CGG repeat expansion that leads to the methylation and transcriptional silencing of the Fragile X mental retardation 1 (fmr1) gene. This results in the loss of Fragile X mental retardation protein (FMRP), an mRNA-binding protein that functions in neuronal mRNA metabolism, namely in the translation of neuronal mRNAs involved in synaptic structure and function. FXS is the most common form of inherited intellectual disability and the largest single genetic cause of autism, affecting 1 in 4000 males and 1 in 8000 females. FMRP plays a crucial role in neural circuit patterning/formation and the regulation of key signalling pathways. FXS is a syndrome is characterized by misregulation of protein synthesis and dysfunction within multiple signalling pathways. Here we implicate two signalling pathways underlying Fragile X Syndrome neuropathology, the cAMP signalling pathway and the Wnt signalling pathway, in cognitive defects. In chapter 2 and 3, we show that FMRP is required for Drosophila stress odour (dSO) avoidance behaviour; dSO is an odour emitted when flies are subjected to electrical or mechanical stress, elicits an innate avoidance behavioural response by Drosophila. Our results suggest that FMRP is required developmentally, specifically in the mushroom body for higher-order processing, in the establishment of neuronal networks and in the regulation of the cAMP signalling cascade that mediates Drosophila stress odour (dSO) sensory processing and avoidance behaviour in Drosophila. Furthermore we show that cyclic adenosine monophosphate (cAMP) is required for avoidance and identify the cAMP cascade as a key signalling pathway underlying avoidance behaviour dysfunction in FXS. Through pharmacological intervention targeting the misregulated cAMP pathway we show that avoidance behaviour can be rescued in FXS flies, demonstrating the ability to ameliorate a developmental abnormality. In chapter 4 we show that over-expression of armadillo/β-catenin results in learning and long-term memory defects and likely contributes to FXS pathology. Furthermore we demonstrate that FXS flies exhibit a learning reversal and long-term memory reversal defect, which may be a result of abnormal armadillo/β-catenin expression resulting in synaptic function and remodeling defects.
Language
English
DOI
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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