The DOI matches its Crossref record; 81 of the 81 references it cites were found in a registry or an index.
Hypersensitivity to mGluR5 and ERK1/2 Leads to Excessive Protein Synthesis in the Hippocampus of a Mouse Model of Fragile X Syndrome
Open accessAbstract
Fragile X syndrome (FXS) is caused by loss of the FMR1 gene product FMRP (fragile X mental retardation protein), a repressor of mRNA translation. According to the metabotropic glutamate receptor (mGluR) theory of FXS, excessive protein synthesis downstream of mGluR5 activation causes the synaptic pathophysiology that underlies multiple aspects of FXS. Here, we use an in vitro assay of protein synthesis in the hippocampus of male Fmr1 knock-out (KO) mice to explore the molecular mechanisms involved in this core biochemical phenotype under conditions where aberrant synaptic physiology has been observed. We find that elevated basal protein synthesis in Fmr1 KO mice is selectively reduced to wild-type levels by acute inhibition of mGluR5 or ERK1/2, but not by inhibition of mTOR (mammalian target of rapamycin). The mGluR5-ERK1/2 pathway is not constitutively overactive in the Fmr1 KO, however, suggesting that mRNA translation is hypersensitive to basal ERK1/2 activation in the absence of FMRP. We find that hypersensitivity to ERK1/2 pathway activation also contributes to audiogenic seizure susceptibility in the Fmr1 KO. These results suggest that the ERK1/2 pathway, and other neurotransmitter systems that stimulate protein synthesis via ERK1/2, represent additional therapeutic targets for FXS.
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“have demonstrated that dampening mGluR5 signalling rescues protein synthesis and many of the classic outcome measures (TABLE 1) used in the mouse and fly models30–35.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [33]
Experimental — accuracy not yet measuredIn the citing paper
“These findings are the basis of human clinical trials that aim to test the efficacy of mGluR5 antagonists for the treating Fragile X syndrome23,56–58.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [57]
In the citing paper
“These findings of deficient mGluR–LTD in mice with deletions in Tsc1 or Tsc2 are in contrast with Fmr1 knockout mice, which have increased mGluR–LTD and excessive protein synthesis57.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [57]
In the citing paper
“We found a small but significant increase in protein synthesis of both FMRP targets in the absence of functional FMRP, similar to results reported for Camk2a by Bear and colleagues in slice cultures (Osterweil et al., 2010), with no significant change in either overall protein synthesis or in the synthesis of the non-target PABP (Figure 6G and Figure S6).”
From FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism (2011) · cites this paper as Osterweil et al., 2010
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Cites
Verkerk, A. J. M. H., Pieretti, M., Sutcliffe, J. S., Fu, Y.-H., Kuhl, D. P. A., Pizzuti, A., Reiner, O., Richards, S., Victoria, M. F., Zhang, F., et al. (1991) · Cell · doi:10.1016/0092-8674(91)90397-h · Cited by 3,481
Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN
Stambolic, V., Suzuki, A., de la Pompa, J. L., Brothers, G. M., Mirtsos, C., Sasaki, T., Ruland, J., Penninger, J. M., Siderovski, D. P., & Mak, T. W. (1998) · Cell · doi:10.1016/s0092-8674(00)81780-8 · Cited by 2,551
eIF4 Initiation Factors: Effectors of mRNA Recruitment to Ribosomes and Regulators of Translation
Gingras, A., Raught, B., & Sonenberg, N. (1999) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.68.1.913 · Cited by 2,103
The mGluR theory of fragile X mental retardation
Bear, M. F., Huber, K. M., & Warren, S. T. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2004.04.009 · Cited by 1,580
Self-citationHara, K., Yonezawa, K., Weng, Q.-P., Kozlowski, M. T., BELHAM, C. M., & Avruch, J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.23.14484 · Cited by 1,370
Altered synaptic plasticity in a mouse model of fragile X mental retardation
Huber, K. M., Gallagher, S. M., Warren, S. T., & Bear, M. F. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.122205699 · Cited by 1,349
Self-citationBrown, V., Jin, P., Ceman, S., Darnell, J. C., O'Donnell, W. T., Tenenbaum, S. A., Jin, X., Feng, Y., Wilkinson, K. D., Keene, J. D., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00568-2 · Cited by 1,109
Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression.
Huber, K., Kayser, M., & Bear, M. (2000) · Science · doi:10.1126/science.288.5469.1254 · Cited by 1,015
Self-citationCorrection of Fragile X Syndrome in Mice
Dölen, G., Osterweil, E., Rao, B. S. S., Smith, G. B., Auerbach, B. D., Chattarji, S., & Bear, M. F. (2007) · Neuron · doi:10.1016/j.neuron.2007.12.001 · Cited by 979
Self-citationThe MEK/ERK cascade: From signaling specificity to diverse functions
Shaul, Y. D., & Seger, R. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.10.005 · Cited by 969
Research works printed but not linked: 1
- 10.1017/S0012162201002833 · DOI · Paper page
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FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism
Darnell, J. C., Van Driesche, S. J., Zhang, C., Hung, K. Y. S., Mele, A., Fraser, C. E., Stone, E. F., Chen, C., Fak, J. J., Chi, S. W., et al. (2011) · Cell · doi:10.1016/j.cell.2011.06.013 · Cited by 2,072
Advancing the understanding of autism disease mechanisms through genetics
de la Torre-Ubieta, L., Won, H., Stein, J. L., & Geschwind, D. H. (2016) · Nature Medicine · doi:10.1038/nm.4071 · Cited by 827
Hagerman, R. J., Berry-Kravis, E., Hazlett, H. C., Bailey, D. B., Moine, H., Kooy, R. F., Tassone, F., Gantois, I., Sonenberg, N., Mandel, J. L., et al. (2017) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2017.65 · Cited by 838
Zoghbi, H. Y., & Bear, M. F. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a009886 · Cited by 797
Self-citationActivity-dependent neuronal signalling and autism spectrum disorder
Ebert, D. H., & Greenberg, M. E. (2013) · Nature · doi:10.1038/nature11860 · Cited by 666
Metadata
- Authors
- Osterweil, E. K., Krueger, D. D., Reinhold, K., & Bear, M. F.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Bear, Mark F.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-11-17
- Volume
- 30
- Issue
- 46
- Pages
- 15616-15627
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3400430
- OpenAlex
- W2092491372
- Cited by
- 384
- References
- 81
- Citations by year
- 2026: 11 · 2025: 20 · 2024: 18 · 2023: 15 · 2022: 17 · 2021: 24 · 2020: 27 · 2019: 23 · 2018: 22 · 2017: 34 · 2016: 33 · 2015: 29 · 2014: 30 · 2013: 31 · 2012: 24
- FWCI
- 14.40
- 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)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Howard Hughes Medical Institute
- FRAXA Research Foundation
- Simons Foundation
- National Institute of Mental Health
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD046943)
- 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, mGluR5, ERK1/2, protein synthesis, hippocampus, metabotropic glutamate receptors, mRNA translation, Fmr1 knockout mice, audiogenic seizures, mTOR, therapeutic target
- MeSH terms
- Animals, Disease Models, Animal, Fragile X Syndrome, Hippocampus, Isoenzymes, Male, Mice, Inbred C57BL, Pyridines, Protein Biosynthesis, Up-Regulation, Receptors, Metabotropic Glutamate, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mice, Fragile X Messenger Ribonucleoprotein 1, Fragile X Mental Retardation Protein, Receptor, Metabotropic Glutamate 5
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