Cited by 251Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchAutism Spectrum Disorder Research

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

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Ronesi, Jennifer A, Collins, Katie A, Hays, Seth A, Tsai, Nien-Pei, Guo, Weirui, Birnbaum, Shari G, Hu, Jia-Hua, Worley, Paul F +2 more·2012·Nature Neuroscience

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.

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  1. [4]Hagerman R Hagerman R Hagerman P The physical and behavioral phenotype Fragile X Syndrome: Diagnosis, Treatment, and Research 2002 3 109 The Johns Hopkins University Press Baltimore

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Authors
Ronesi, J. A., Collins, K. A., Hays, S. A., Tsai, N.-P., Guo, W., Birnbaum, S. G., Hu, J.-H., Worley, P. F., Gibson, J. R., & Huber, K. M.
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • Johns Hopkins University (US)
Corresponding author
Huber, Kimberly M
Venue
Nature Neuroscience
Published
2012-01-22
Volume
15
Issue
3
Pages
431-440
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
OpenAlex
W2134906491
Cited by
251
References
50
Citations by year
2026: 4 · 2025: 6 · 2024: 9 · 2023: 11 · 2022: 13 · 2021: 16 · 2020: 20 · 2019: 18 · 2018: 17 · 2017: 23 · 2016: 27 · 2015: 21 · 2014: 24 · 2013: 25 · 2012: 16
FWCI
16.52
Type
journal article
Language
en
Open access
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Autism Speaks (AS2086)
  • National Institute of General Medical Sciences (GM008203, T32GM008203)
  • National Institute of Neurological Disorders and Stroke (R01NS045711, NS045711)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD052731, HD-052731, HD056370, R01HD056370)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
fragile X syndrome, mGluR5, Homer1a, Fmr1 knockout mice, intellectual disability, autism spectrum disorder, synaptic depression, translational regulation, FMRP, cognitive impairment
MeSH terms
Homer Scaffolding Proteins, Analysis of Variance, Animals, Carrier Proteins, Cycloheximide, Disease Models, Animal, Electric Stimulation, Exploratory Behavior, Fragile X Syndrome, Gene Expression Regulation, Hippocampus, Methoxyhydroxyphenylglycol, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Nerve Net, Peptides, Physics, Protein Synthesis Inhibitors, Serine, Signal Transduction, Long-Term Potentiation, Receptors, Metabotropic Glutamate, Patch-Clamp Techniques, Rats, Long-Evans, Immunoprecipitation, Mice, Rats, Fragile X Messenger Ribonucleoprotein 1, TOR Serine-Threonine Kinases, Receptor, Metabotropic Glutamate 5, In Vitro Techniques

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