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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD046943-08
Application #
8291904
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Urv, Tiina K
Project Start
2003-09-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$295,285
Indirect Cost
$116,005
Name
Massachusetts Institute of Technology
Department
Miscellaneous
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Stoppel, Laura J; Auerbach, Benjamin D; Senter, Rebecca K et al. (2017) ?-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X. Cell Rep 18:2807-2814
Tian, Di; Stoppel, Laura J; Heynen, Arnold J et al. (2015) Contribution of mGluR5 to pathophysiology in a mouse model of human chromosome 16p11.2 microdeletion. Nat Neurosci 18:182-4
Sidorov, Michael S; Kaplan, Eitan S; Osterweil, Emily K et al. (2015) Metabotropic glutamate receptor signaling is required for NMDA receptor-dependent ocular dominance plasticity and LTD in visual cortex. Proc Natl Acad Sci U S A 112:12852-7
Sidorov, M S; Krueger, D D; Taylor, M et al. (2014) Extinction of an instrumental response: a cognitive behavioral assay in Fmr1 knockout mice. Genes Brain Behav 13:451-8
Chubykin, Alexander A; Roach, Emma B; Bear, Mark F et al. (2013) A cholinergic mechanism for reward timing within primary visual cortex. Neuron 77:723-35
Osterweil, Emily K; Chuang, Shih-Chieh; Chubykin, Alexander A et al. (2013) Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron 77:243-50
Krueger, Dilja D; Bear, Mark F (2011) Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annu Rev Med 62:411-29
Javitt, Daniel C; Schoepp, Darryle; Kalivas, Peter W et al. (2011) Translating glutamate: from pathophysiology to treatment. Sci Transl Med 3:102mr2
Auerbach, Benjamin D; Osterweil, Emily K; Bear, Mark F (2011) Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480:63-8
Krueger, Dilja D; Osterweil, Emily K; Chen, Stephanie P et al. (2011) Cognitive dysfunction and prefrontal synaptic abnormalities in a mouse model of fragile X syndrome. Proc Natl Acad Sci U S A 108:2587-92

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