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

Jennifer A. Ronesi, Katie A. Collins, Seth A. Hays, Nien Pei Tsai, Weirui Guo, Shari G. Birnbaum, Jia Hua Hu, Paul F. Worley, Jay R. Gibson, Kimberly M. Huber

Research output: Contribution to journalArticle

142 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)431-440
Number of pages10
JournalNature Neuroscience
Volume15
Issue number3
DOIs
StatePublished - Mar 2012

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Metabotropic Glutamate 5 Receptor
Fragile X Syndrome
Autistic Disorder
Phenotype
Long-Term Synaptic Depression
Fragile X Mental Retardation Protein
Intellectual Disability
Protein Isoforms

ASJC Scopus subject areas

  • Neuroscience(all)

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Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. / Ronesi, Jennifer A.; Collins, Katie A.; Hays, Seth A.; Tsai, Nien Pei; Guo, Weirui; Birnbaum, Shari G.; Hu, Jia Hua; Worley, Paul F.; Gibson, Jay R.; Huber, Kimberly M.

In: Nature Neuroscience, Vol. 15, No. 3, 03.2012, p. 431-440.

Research output: Contribution to journalArticle

Ronesi, Jennifer A. ; Collins, Katie A. ; Hays, Seth A. ; Tsai, Nien Pei ; Guo, Weirui ; Birnbaum, Shari G. ; Hu, Jia Hua ; Worley, Paul F. ; Gibson, Jay R. ; Huber, Kimberly M. / Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. In: Nature Neuroscience. 2012 ; Vol. 15, No. 3. pp. 431-440.
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