Fragile X syndrome (FXS) is the most common form of heritable human 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 poorly understood. During the previous grant period we tested the proposal that many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. We generated Fmr1 mutant (KO) mice with a 50% reduction in mGluR5 expression and discovered that a wide range of phenotypes with relevance to the human disorder were brought significantly closer to normal. Our findings have significant therapeutic implications for fragile X and related developmental disorders, and have inspired human clinical trials of mGluR5 antagonists for the treatment of FXS. Our objective in the next grant period is to gain additional insights from the mouse model of the disease that can guide treatment in humans. We have two specific aims:
Aim 1 : Does postnatal inhibition of mGluR5 prevent emergence of fragile X phenotypes? Aim 2: Does late onset inhibition of mGluR5 reverse fragile X phenotypes?

Public Health Relevance

Fragile X syndrome is caused by mutation of a gene involved in regulation of protein synthesis at synaptic connections between neurons. A genetic strategy to restore balanced synaptic protein synthesis has been remarkably successful in correcting widely varied mutant phenotypes in mouse models of the disease. Further insight gained by the studies in animal models of fragile X are likely to suggest novel therapeutic approaches, not only for human fragile X, but also for autism and mental retardation of unknown etiology.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Urv, Tiina K
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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