Abstract
Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acoustic Stimulation / adverse effects
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Animals
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Behavior, Animal / physiology
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Disease Models, Animal
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Fragile X Mental Retardation Protein / genetics*
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Fragile X Syndrome / genetics*
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Fragile X Syndrome / pathology
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Fragile X Syndrome / physiopathology
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Fragile X Syndrome / therapy*
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Functional Laterality / physiology
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Gene Expression Regulation / genetics
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Heterozygote
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Learning / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Multivariate Analysis
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Neuronal Plasticity
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Neurons / pathology
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Neurons / ultrastructure
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Phenotype
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate / deficiency
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Receptors, Metabotropic Glutamate / genetics*
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Seizures / etiology
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Visual Cortex / physiopathology
Substances
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Fmr1 protein, mouse
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GRM5 protein, human
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Grm5 protein, mouse
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate
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Fragile X Mental Retardation Protein