Abstract
Enhanced metabotropic glutamate receptor subunit 5 (mGluR5) function is causally associated with the pathophysiology of fragile X syndrome, a leading inherited cause of intellectual disability and autism. Here we provide evidence that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in the fragile X syndrome mouse model, Fmr1 knockout (Fmr1(-/y)). In Fmr1(-/y) mice, mGluR5 was less associated with long Homer isoforms but more associated with the short Homer1a. Genetic deletion of Homer1a restored mGluR5-long Homer scaffolds and corrected several phenotypes in Fmr1(-/y) mice, including altered mGluR5 signaling, neocortical circuit dysfunction and behavior. Acute, peptide-mediated disruption of mGluR5-Homer scaffolds in wild-type mice mimicked many Fmr1(-/y) phenotypes. In contrast, Homer1a deletion did not rescue altered mGluR-dependent long-term synaptic depression or translational control of target mRNAs of fragile X mental retardation protein, the gene product of Fmr1. Our findings reveal new functions for mGluR5-Homer interactions in the brain and delineate distinct mechanisms of mGluR5 dysfunction in a mouse model of cognitive dysfunction and autism.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cycloheximide / pharmacology
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Disease Models, Animal
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Electric Stimulation / methods
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Exploratory Behavior / physiology
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Fragile X Mental Retardation Protein
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Fragile X Syndrome / genetics
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Fragile X Syndrome / metabolism*
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Fragile X Syndrome / pathology
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Fragile X Syndrome / physiopathology
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Gene Expression Regulation / genetics
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Gene Expression Regulation / physiology*
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Hippocampus / pathology
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Hippocampus / physiopathology
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Homer Scaffolding Proteins
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Immunoprecipitation
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In Vitro Techniques
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Long-Term Potentiation / drug effects
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Long-Term Potentiation / genetics
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Methoxyhydroxyphenylglycol / analogs & derivatives
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Methoxyhydroxyphenylglycol / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation
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Nerve Net / drug effects
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Nerve Net / physiology
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Patch-Clamp Techniques
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Peptides / pharmacology
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Physics
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Protein Synthesis Inhibitors / pharmacology
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Rats
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Rats, Long-Evans
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate / chemistry
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Receptors, Metabotropic Glutamate / metabolism*
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Serine / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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TOR Serine-Threonine Kinases / metabolism
Substances
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Carrier Proteins
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Fmr1 protein, mouse
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Grm5 protein, mouse
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Grm5 protein, rat
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Homer Scaffolding Proteins
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Peptides
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Protein Synthesis Inhibitors
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate
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Fragile X Mental Retardation Protein
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Serine
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Methoxyhydroxyphenylglycol
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Cycloheximide
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mTOR protein, mouse
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TOR Serine-Threonine Kinases
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3,4-dihydroxyphenylglycol