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

Nat Neurosci. 2012 Jan 22;15(3):431-40, S1. doi: 10.1038/nn.3033.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cycloheximide / pharmacology
  • Disease Models, Animal
  • Electric Stimulation / methods
  • Exploratory Behavior / physiology
  • Fragile X Mental Retardation Protein
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / metabolism*
  • Fragile X Syndrome / pathology
  • Fragile X Syndrome / physiopathology
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology*
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Homer Scaffolding Proteins
  • Immunoprecipitation
  • In Vitro Techniques
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / genetics
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Nerve Net / drug effects
  • Nerve Net / physiology
  • Patch-Clamp Techniques
  • Peptides / pharmacology
  • Physics
  • Protein Synthesis Inhibitors / pharmacology
  • Rats
  • Rats, Long-Evans
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / chemistry
  • Receptors, Metabotropic Glutamate / metabolism*
  • Serine / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Carrier Proteins
  • Fmr1 protein, mouse
  • Grm5 protein, mouse
  • Grm5 protein, rat
  • Homer Scaffolding Proteins
  • Peptides
  • Protein Synthesis Inhibitors
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Fragile X Mental Retardation Protein
  • Serine
  • Methoxyhydroxyphenylglycol
  • Cycloheximide
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • 3,4-dihydroxyphenylglycol