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

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

Authors

  • Ronesi JA
  • Collins KA
  • Hays SA
  • Tsai NP
  • Guo W
  • Birnbaum SG
  • Hu JH
  • Worley PF
  • Gibson JR
  • Huber KM

Journal

Nature neuroscience

Publication Data

March 24, 2012

Associated Grants

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

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
  • 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