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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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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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