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Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome
Open accessAbstract
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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“Enhanced mTOR signaling and cap-dependent translation initiation complex are found also in mouse models of human Fragile X Syndrome, characterized by the lack of FMRP.85, 86, 87”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [86]
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Cites
1 retracted
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Zoghbi, H. Y., & Bear, M. F. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a009886 · Cited by 797
Um, J. W., Kaufman, A. C., Kostylev, M., Heiss, J. K., Stagi, M., Takahashi, H., Kerrisk, M. E., Vortmeyer, A., Wisniewski, T., Koleske, A. J., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.036 · Cited by 572
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Altered Neuronal and Circuit Excitability in Fragile X Syndrome
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Exaggerated translation causes synaptic and behavioural aberrations associated with autism
Santini, E., Huynh, T. N., MacAskill, A. F., Carter, A. G., Pierre, P., Ruggero, D., Kaphzan, H., & Klann, E. (2012) · Nature · doi:10.1038/nature11782 · Cited by 383
Metadata
- 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
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2012-01-22
- Volume
- 15
- Issue
- 3
- Pages
- 431-440
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC3288402
- 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
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- 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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