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Genetic interaction between Fmr1 and Grm5 : a role for mGluR5 in the pathogenesis of fragile X syndrome.

Author: Gül Dölen
Publisher: 2008.
Dissertation: Ph. D. Brown University 2008
Edition/Format:   Thesis/dissertation : Thesis/dissertation : Manuscript   Archival Material : English
Summary:
Fragile X syndrome (FXS) is the leading inherited cause of mental retardation and an identified cause of autism. It is unknown how disruption of brain function by a mutation in FMR1 leads to the syndrome that includes altered neural development, cognitive impairment, and childhood epilepsy. Currently, there is no effective treatment for FXS and the prospects for therapy by gene replacement are not promising. Future
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Genre/Form: Academic theses
Material Type: Thesis/dissertation, Manuscript, Internet resource
Document Type: Book, Archival Material, Internet Resource
All Authors / Contributors: Gül Dölen
ISBN: 9780549674719 0549674713
OCLC Number: 549751831
Notes: Advisor : Mark F. Bear.
Description: 225 leaves : illustrations (some color) ; 28 cm
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Abstract:

Fragile X syndrome (FXS) is the leading inherited cause of mental retardation and an identified cause of autism. It is unknown how disruption of brain function by a mutation in FMR1 leads to the syndrome that includes altered neural development, cognitive impairment, and childhood epilepsy. Currently, there is no effective treatment for FXS and the prospects for therapy by gene replacement are not promising. Future therapeutic approaches must therefore be based on a more complete understanding of the pathogenesis of the disease.

Fragile X mental retardation protein (FMRP) and mRNA are enriched postsynaptically in the brain, particularly at synapses that use the major excitatory neurotransmitter glutamate, so much attention has been focused on synaptic dysfunction in FXS. Recently a "metabotropic glutamate receptor (mGluR) theory" of FXS pathogenesis has been proposed, based on the following four observations: (i) FMRP can function as a repressor of mRNA translation at synapses; (ii) synaptic protein synthesis is stimulated by activation of group I (Gp1) mGluRs; (iii) many of the lasting consequences of activating Gp1 mGluRs depend on synaptic mRNA translation; and (iv) in the absence of FMRP, several protein synthesis-dependent consequences of activating mGluRs are exaggerated. These findings have led to the idea that FMRP and Gp1 mGluRs normally work in functional opposition, and that in the absence of FMRP, unchecked mGluR-dependent protein synthesis leads to the pathogenesis of FXS.

The goal of these studies was to test a key prediction of the mGluR theory---that aspects of FXS can be corrected by down-regulating signaling through group I mGluRs. Although a range of phenotypes were studied, one way to conceptualize the constellation of findings is that FXS is a disorder of excess---excessive sensitivity to environmental change, synaptic connectivity, memory extinction, protein synthesis, body growth, and excitability---and these excesses can be corrected by reducing mGluR5 signaling. The data show unambiguously that mGluR5 and FMRP act as an opponent pair in several functional contexts, and support the theory that many CNS symptoms in FXS are accounted for by unbalanced activation of Gp1 mGluRs. These findings have major therapeutic implications for FXS syndrome and autism.

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