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Evidence for a Fragile X Mental Retardation Protein-Mediated Translational Switch in Metabotropic Glutamate Receptor-Triggered Arc Translation and Long-Term Depression
Open accessAbstract
Group 1 metabotropic glutamate receptor (mGluR)-stimulated protein synthesis and long-term synaptic depression (mGluR-LTD) are altered in the mouse model of fragile X syndrome,Fmr1 knock-out (KO) mice.Fmr1 encodes fragile X mental retardation protein (FMRP), a dendritic RNA binding protein that functions, in part, as a translational suppressor. It is unknown whether and how FMRP acutely regulates LTD and/or the rapid synthesis of new proteins required for LTD, such as the activity-regulated cytoskeletal-associated protein (Arc). The protein phosphatase PP2A dephosphorylates FMRP, which contributes to translational activation of some target mRNAs. Here, we report that PP2A and dephosphorylation of FMRP at S500 are required for an mGluR-induced, rapid (5 min) increase in dendritic Arc protein and LTD in rat and mouse hippocampal neurons. In Fmr1 KO neurons, basal, dendritic Arc protein levels and mGluR-LTD are enhanced, but mGluR-triggered Arc synthesis is absent. Lentiviral-mediated expression of wild-type FMRP in Fmr1 KO neurons suppresses basal dendritic Arc levels and mGluR-LTD, and restores rapid mGluR-triggered Arc synthesis. A phosphomimic of FMRP (S500D) suppresses steady-state dendritic Arc levels but does not rescue mGluR-induced Arc synthesis. A dephosphomimic of FMRP (S500A) neither suppresses dendritic Arc nor supports mGluR-induced Arc synthesis. Accordingly, S500D-FMRP expression in Fmr1 KO neurons suppresses mGluR-LTD, whereas S500A-FMRP has no effect. These data support a model in which phosphorylated FMRP functions to suppress steady-state translation of Arc and LTD. Upon mGluR activation of PP2A, FMRP is rapidly dephosphorylated, which contributes to rapid new synthesis of Arc and mGluR-LTD.
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“Furthermore, PP2A not only removes the FMRP brake (Niere et al., 2012) but also interferes with NMDA signaling by dephosphorylating and deactivating ERK1/2 (Alessi et al., 1995).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Niere et al., 2012
In the citing paper
“This in turn will increase the abundance of regulatory proteins such as Arc, CaMKIIα, PSD95, and CaMKIIβ (Darnell et al., 2011; Muddashetty et al., 2011; Niere et al., 2012; Park et al., 2008; Stefanovic et al., 2015), setting up the spine for a binary decision, to undergo LTD or LTP.”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Niere et al., 2012
In the citing paper
“In Fmr1 knockout mice, the dynamic translation of Arc mRNA in response to stimulation is impaired59,61, and the basal level of the Arc protein in dendrites is elevated61.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [61]
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“stimulus-regulated phosphorylation or dephosphorylation of FMRP alters its ability to suppress mRNA translation61,73–75.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [61]
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Metadata
- Authors
- Niere, F., Wilkerson, J. R., & Huber, K. M.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-04-25
- Volume
- 32
- Issue
- 17
- Pages
- 5924-5936
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3349238
- OpenAlex
- W1976666730
- Cited by
- 153
- References
- 60
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 4 · 2023: 8 · 2022: 10 · 2021: 10 · 2020: 12 · 2019: 12 · 2018: 10 · 2017: 16 · 2016: 11 · 2015: 11 · 2014: 18 · 2013: 16 · 2012: 6
- FWCI
- 9.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Autism Speaks (AS2086)
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS045711, NS045711)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD06212001, R01HD052731, F32HD062120, HD-052731, HD052731S1)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- fragile X syndrome, FMRP, metabotropic glutamate receptors, long-term depression, Arc, protein synthesis, protein phosphatase 2A, translational regulation, dendritic protein synthesis, Fmr1 knockout mice, hippocampal neurons, RNA-binding proteins
- MeSH terms
- Animals, Animals, Newborn, Cells, Cultured, Cytoskeletal Proteins, Dendrites, Electric Stimulation, Enzyme Inhibitors, Gene Expression Regulation, Hippocampus, Humans, Methoxyhydroxyphenylglycol, Mice, Inbred C57BL, Models, Biological, Nerve Tissue Proteins, Neurons, Phosphorylation, Serine, Tetrodotoxin, Time Factors, Transfection, Protein Biosynthesis, Receptors, Metabotropic Glutamate, Mice, Knockout, Patch-Clamp Techniques, Okadaic Acid, Excitatory Postsynaptic Potentials, Rats, Long-Evans, Sodium Channel Blockers, Long-Term Synaptic Depression, Green Fluorescent Proteins, Mice, Rats, Fragile X Messenger Ribonucleoprotein 1, Fragile X Mental Retardation Protein, Protein Phosphatase 2, In Vitro Techniques
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