Fragile X syndrome (FXS) is the leading cause of inherited mental retardation and developmental delay. In the vast majority of cases, this X-linked disorder is due to a CGG expansion in the 5' untranslated region of the fmr-1 gene and the resulting decreased expression of its associated protein, FMRP (Fragile X associated Mental Retardation Protein). FXS is characterized by a number of cognitive, behavioural, anatomical, and biological abnormalities. This monogenic disorder provides a unique opportunity to study the consequence of a mutation in a single gene on the development and proper functioning of the CNS. / Histological work on FMRP expression in the monkey lateral geniculate nucleus (LGN) has revealed differential staining in the magnocellular and parvocellular layers, with increased expression in the magnocellular layers (Kogan, Boutet, Cornish, Zangenehpour, & Mullen, 2004). In individuals with fragile X, this differential expression pattern is correlated at the behavioural level with impairments in the M but not the P-visual pathway processing. These findings by Kogan and colleagues, led to the hypothesis that brain regions that express high levels of FMRP are particularly susceptible to its reduced expression, as occurs in FXS. It was therefore of interest to extend this work to determine the pattern of FMRP expression throughout the monkey brain, with the aim of identifying the brain structures most susceptible to reduced expression of the fmr-1 gene product. / The current focus on the role of FMRP in RNA translation and neuronal maturation makes it timely to assemble the extant information on how reduced expression of the fmr-1 gene leads to neuronal dysmorphology. The first section of this manuscript offers a summary of recent genetic, neuroanatomical, and behavioural studies of fragile X syndrome, and provides potential mechanisms to account for the pleiotropic phenotype of this disorder. The following section presents a detailed account of the FMRP expression profile in the monkey brain, and reveals the striking correlation between the expression of the protein and behavioural deficits associated with its reduced expression, as occurs in FXS. / The last chapter of this manuscript offers insight into future trends in FXS research. A number of electrophysiological and behavioural studies point to a particular involvement of the metabotropic glutamatergic system in FXS, with a preeminent role for metabotropic glutamate receptor type V (mGluR5). The involvement of this receptor in FXS and the potential therapeutic implications of pharmacological regulation of this receptor will be discussed. / There is a body of work pointing to the remarkable behavioural similarities between FXS and autism. While FXS is a single-gene disorder, autism is associated with a number of genes, which have not yet been precisely identified. The final section of this manuscript delineates the neuroanatomical, behavioural, and linguistic overlap, as well as the differences between the two conditions. Finally, this section affords some insight as to how FXS, a single-gene disorder, may assist us in our understanding of autism. / Keywords: Fragile X Syndrome (FXS), fmr-1 mutation, lateral geniculate nucleus (LGN), anterior cingulated cortex (ACC), dentate gyros (DG), superior frontal gyrus (SFG), cerebellum, metabotropic glutamate receptor type V (mGluR5), postsynaptic density protein 95 (PSD-95), dendritic spine, autism / Abbreviations: fragile X syndrome (FXS), long-term potentiation (LTP), long-term depression (LTD), RNA-binding protein (RBP), lateral geniculate nucleus (LGN), anterior cingulated cortex (ACC), dentate gyrus (DG), superior frontal gyrus (SFG), metabotropic glutamate receptor type V (mGluR5), postsynaptic density protein 95 (PSD-95), region of interest (ROI), deep cerebellar nucleus (DCN).
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.101859 |
| Date | January 2007 |
| Creators | Koukoui, Sophia Dona. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Psychology.) |
| Rights | © Sophia Dona Koukoui, 2007 |
| Relation | alephsysno: 002666625, proquestno: AAIMR38410, Theses scanned by UMI/ProQuest. |
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