Abstract
Genetic deletion of fragile X mental retardation protein (FMRP) has been shown to enhance mGluR-dependent long-term depression (LTD). Herein, we demonstrate that mGluR-LTD induces a transient, translation-dependent increase in FMRP that is rapidly degraded by the ubiquitin-proteasome pathway. Moreover, proteasome inhibitors abolished mGluR-LTD, and LTD was absent in mice that overexpress human FMRP. Neither translation nor proteasome inhibitors blocked the augmentation of mGluR-LTD in FMRP-deficient mice. In addition, mGluR-LTD is associated with rapid increases in the protein levels of FMRP target mRNAs in wild-type mice. Interestingly, the basal levels of these proteins were elevated and their synthesis was improperly regulated during mGluR-LTD in FMRP-deficient mice. Our findings indicate that hippocampal mGluR-LTD requires the rapid synthesis and degradation of FMRP and that mGluR-LTD triggers the synthesis of FMRP binding mRNAs. These findings indicate that the translation, ubiquitination, and proteolysis of FMRP functions as a dynamic regulatory system for controlling synaptic plasticity.
Publication types
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Comparative Study
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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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Animals
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Animals, Newborn
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Anisomycin / pharmacology
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Benzoates / pharmacology
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Blotting, Western / methods
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Cysteine Proteinase Inhibitors / pharmacology
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Dose-Response Relationship, Drug
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Drug Interactions
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Excitatory Amino Acid Antagonists / pharmacology
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Fluorescent Antibody Technique / methods
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Fragile X Mental Retardation Protein / genetics
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Fragile X Mental Retardation Protein / metabolism*
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Glycine / analogs & derivatives
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Glycine / pharmacology
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In Vitro Techniques
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Leupeptins / pharmacology
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Long-Term Synaptic Depression / drug effects
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Long-Term Synaptic Depression / physiology*
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Male
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Methoxyhydroxyphenylglycol / analogs & derivatives
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Methoxyhydroxyphenylglycol / pharmacology
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Mice
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Mice, Knockout
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Microtubule-Associated Proteins / metabolism
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Models, Biological
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Proteasome Endopeptidase Complex / metabolism*
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Protein Biosynthesis / drug effects
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Protein Biosynthesis / physiology*
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Protein Synthesis Inhibitors / pharmacology
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Pyridines / pharmacology
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RNA, Messenger / metabolism
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Receptors, Metabotropic Glutamate / physiology*
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Signal Transduction / drug effects
Substances
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Benzoates
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Cysteine Proteinase Inhibitors
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Excitatory Amino Acid Antagonists
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Fmr1 protein, mouse
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Leupeptins
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Microtubule-Associated Proteins
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Mtap2 protein, mouse
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Protein Synthesis Inhibitors
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Pyridines
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RNA, Messenger
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Receptors, Metabotropic Glutamate
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Fragile X Mental Retardation Protein
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alpha-methyl-4-carboxyphenylglycine
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Methoxyhydroxyphenylglycol
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Anisomycin
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6-methyl-2-(phenylethynyl)pyridine
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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Glycine
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3,4-dihydroxyphenylglycol