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Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome.

Nature neuroscience | Jan 22, 2012

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.

Pubmed ID: 22267161 RIS Download

Mesh terms: Analysis of Variance | Animals | Carrier Proteins | Cycloheximide | Disease Models, Animal | Electric Stimulation | Exploratory Behavior | Fragile X Mental Retardation Protein | Fragile X Syndrome | Gene Expression Regulation | Hippocampus | Homer Scaffolding Proteins | Immunoprecipitation | In Vitro Techniques | Long-Term Potentiation | Methoxyhydroxyphenylglycol | Mice | Mice, Inbred C57BL | Mice, Transgenic | Mutation | Nerve Net | Patch-Clamp Techniques | Peptides | Physics | Protein Synthesis Inhibitors | Rats | Rats, Long-Evans | Receptor, Metabotropic Glutamate 5 | Receptors, Metabotropic Glutamate | Serine | Signal Transduction | TOR Serine-Threonine Kinases

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Associated grants

  • Agency: NICHD NIH HHS, Id: R01 HD056370
  • Agency: NICHD NIH HHS, Id: R01 HD052731
  • Agency: NICHD NIH HHS, Id: HD056370
  • Agency: NINDS NIH HHS, Id: R01 NS045711
  • Agency: NICHD NIH HHS, Id: HD052731
  • Agency: Autism Speaks, Id: AS2086
  • Agency: NIGMS NIH HHS, Id: GM008203
  • Agency: NINDS NIH HHS, Id: NS045711
  • Agency: NINDS NIH HHS, Id: R01 NS045711-09
  • Agency: NICHD NIH HHS, Id: R01 HD056370-03
  • Agency: NIGMS NIH HHS, Id: T32 GM008203

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