Synaptic regulation of protein synthesis and the fragile X protein
Open accessAbstract
Protein synthesis occurs in neuronal dendrites, often near synapses. Polyribosomal aggregates often appear in dendritic spines, particularly during development. Polyribosomal aggregates in spines increase during experience-dependent synaptogenesis, e.g., in rats in a complex environment. Some protein synthesis appears to be regulated directly by synaptic activity. We use “synaptoneurosomes,” a preparation highly enriched in pinched-off, resealed presynaptic processes attached to resealed postsynaptic processes that retain normal functions of neurotransmitter release, receptor activation, and various postsynaptic responses including signaling pathways and protein synthesis. We have found that, when synaptoneurosomes are stimulated with glutamate or group I metabotropic glutamate receptor agonists such as dihydroxyphenylglycine, mRNA is rapidly taken up into polyribosomal aggregates, and labeled methionine is incorporated into protein. One of the proteins synthesized is FMRP, the protein that is reduced or absent in fragile X mental retardation syndrome. FMRP has three RNA-binding domains and reportedly binds to a significant number of mRNAs. We have found that dihydroxyphenylglycine-activated protein synthesis in synaptoneurosomes is dramatically reduced in a knockout mouse model of fragile X syndrome, which cannot produce full-length FMRP, suggesting that FMRP is involved in or required for this process. Studies of autopsy samples from patients with fragile X syndrome have indicated that dendritic spines may fail to assume a normal mature size and shape and that there are more spines per unit dendrite length in the patient samples. Similar findings on spine size and shape have come from studies of the knockout mouse. Study of the development of the somatosensory cortical region containing the barrel-like cell arrangements that process whisker information suggests that normal dendritic regression is impaired in the knockout mouse. This finding suggests that FMRP may be required for the normal processes of maturation and elimination to occur in cerebral cortical development.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
FMRP is required for type 1 mGluR-dependent translation of synaptic proteins, including FMRP and PSD-95.
“FMRP is required for type 1 metabotropic glutamate receptor (mGluR)–dependent translation of synaptic proteins, including FMRP and postsynaptic density 95 (PSD-95) [21,22].”
From FMRP Mediates mGluR5-Dependent Translation of Amyloid Precursor Protein (2007) · cites this paper as [21]
The paper’s Abstract reports that group I mGluR stimulation induces synaptoneurosomal protein synthesis, including FMRP, and that this response is dramatically reduced in mice lacking full-length FMRP. It describes FMRP as possibly involved in or required for the response, rather than establishing an unqualified requirement. No passage found for PSD-95 or postsynaptic density 95 supports its inclusion. (LLM, conf=0.88)
Experimental — accuracy not yet measuredmGluR activation rapidly derepresses APP synthesis.
“mGluR activation rapidly derepresses APP synthesis as shown for FMRP and PSD-95 [21,22].”
From FMRP Mediates mGluR5-Dependent Translation of Amyloid Precursor Protein (2007) · cites this paper as [21]
The Abstract reports that mGluR agonist stimulation increased FMRP in synaptoneurosomes within 2–5 minutes, supporting the FMRP example attached to this citation. It does not report APP synthesis or establish that the increase occurs through derepression. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Experience and brain development
Greenough, W. T., Black, J. E., & Wallace, C. S. (1987) · Child Development · doi:10.2307/1130197 · Cited by 1,398 · see citing works
Self-citationThe development of ocular dominance columns in normal and visually deprived monkeys
Le Vay, S., Wiesel, T. N., & Hubel, D. H. (1980) · Journal of Comparative Neurology · doi:10.1002/cne.901910102 · Cited by 1,123 · see citing works
Abnormal dendritic spines in fragile X knockout mice: Maturation and pruning deficits
Comery, T. A., Harris, J. B., Willems, P. J., Oostra, B. A., Irwin, S. A., Weiler, I. J., & Greenough, W. T. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.10.5401 · Cited by 1,046 · see citing works
Self-citationWeiler, I. J., Irwin, S. A., Klintsova, A. Y., Spencer, C. M., Brazelton, A. D., Miyashiro, K., Comery, T. A., Patel, B., Eberwine, J., & Greenough, W. T. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.10.5395 · Cited by 644 · see citing works
Analysis of neocortex in three males with the Fragile X syndrome
Hinton, V. J., Brown, W. T., Wisniewski, K., & Rudelli, R. D. (1991) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320410306 · Cited by 527 · see citing works
Turner, A. M., & Greenough, W. T. (1985) · Brain Research · doi:10.1016/0006-8993(85)90525-6 · Cited by 459 · see citing works
Self-citationAdult fragile X syndrome: Clinico-neuropathologic findings
Rudelli, R. D., Brown, W. T., Wisniewski, K., Jenkins, E. C., Laure-Kamionowska, M., Connell, F., & Wisniewski, H. M. (1985) · Acta Neuropathologica · doi:10.1007/bf00687814 · Cited by 362 · see citing works
The fra(X) syndrome: Neurological, electrophysiological, and neuropathological abnormalities
Wisniewski, K. E., Segan, S. M., Miezejeski, C. M., Sersen, E. A., & Rudelli, R. D. (1991) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320380267 · Cited by 261 · see citing works
Flagged first, then by citations
Research works printed but not linked: 28
- [1]Greenough W T, Black J E, Wallace C. Child Dev. 1987;58:539–559. [PubMed] [Google Scholar]
- [3]Greenough W T, Chang F-L F. Dev Brain Res. 1988;43:148–152. doi: 10.1016/0165-3806(88)90160-5. [DOI] [PubMed] [Google Scholar] · DOI
- [4]Steward O, Levy W. J Neurosci. 1982;2:284–291. doi: 10.1523/JNEUROSCI.02-03-00284.1982. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
- [5]Steward O, Falk P. J Neurosci. 1986;6:412–423. doi: 10.1523/JNEUROSCI.06-02-00412.1986. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [6]Steward O. J Neurosci. 1983;3:177–188. doi: 10.1523/JNEUROSCI.03-01-00177.1983. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [8]Black J E, Isaacs K R, Anderson B J, Alcantara A A, Greenough W T. Proc Natl Acad Sci USA. 1990;87:5568–5572. doi: 10.1073/pnas.87.14.5568. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
- [9]Kleim J A, Lussnig E, Schwarz E R, Comery T A, Greenough W T. J Neurosci. 1996;16:4529–4535. doi: 10.1523/JNEUROSCI.16-14-04529.1996. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [10]Greenough W T, Hwang H-M, Gorman C. Proc Natl Acad Sci USA. 1985;82:4549–4552. doi: 10.1073/pnas.82.13.4549. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [11]Hollingsworth E B, McNeal E T, Burton J L, Williams R J, Daly J W, Creveling C R. J Neurosci. 1985;5:2240–2253. doi: 10.1523/JNEUROSCI.05-08-02240.1985. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [12]Weiler I J, Greenough W T. Mol Cell Neurosci. 1991;2:305–314. doi: 10.1016/1044-7431(91)90060-2. [DOI] [PubMed] [Google Scholar] · DOI
- [13]Weiler I J, Greenough W T. Proc Natl Acad Sci USA. 1993;90:7168–7171. doi: 10.1073/pnas.90.15.7168. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [14]Berthele A, Platzer S, Laurie D J, Weis S, Sommer B, Zieglgansberger W, Conrad B, Tolle T R. NeuroReport. 1999;10:3861–3867. doi: 10.1097/00001756-199912160-00026. [DOI] [PubMed] [Google Scholar] · DOI
- [15]Liu X B, Munoz A, Jones E G. J Comp Neurol. 1998;395:450–465. doi: 10.1002/(sici)1096-9861(19980615)395:4<450::aid-cne3>3.0.co;2-0. [DOI] [PubMed] [Google Scholar] · DOI
- [16]Porter J T, McCarthy K D. Glia. 1995;13:101–112. doi: 10.1002/glia.440130204. [DOI] [PubMed] [Google Scholar] · DOI
- [17]Miyashiro K, Dichter M, Eberwine J. Proc Natl Acad Sci USA. 1994;91:10800–10804. doi: 10.1073/pnas.91.23.10800. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [19]Brown W T. Am J Hum Genet. 1996;58:903–905. [PMC free article] [PubMed] [Google Scholar]
- [20]Hagerman R J, Cronister A, editors. Fragile X Syndrome: Diagnosis, Treatment, and Research. Baltimore: Johns Hopkins Univ. Press; 1996. [Google Scholar]
- [21]Steward O, Schuman E M. Ann Rev Neurosci. 2001;24:299–325. doi: 10.1146/annurev.neuro.24.1.299. [DOI] [PubMed] [Google Scholar] · DOI
- [22]Shestakova E A, Singer R H, Condeelis J. Proc Natl Acad Sci USA. 2001;98:7045–7050. doi: 10.1073/pnas.121146098. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [23]Knopf P M, Dintzis H M. Biochemistry. 1965;4:1427–1434. doi: 10.1021/bi00883a030. [DOI] [PubMed] [Google Scholar] · DOI
- [24]Hunt T, Hunter T, Munro A. J Mol Biol. 1969;43:123–133. doi: 10.1016/0022-2836(69)90083-7. [DOI] [PubMed] [Google Scholar] · DOI
- [25]Irwin S A, Swain R A, Christmon C A, Chakravarti A, Weiler I J, Greenough W T. Neurobiol Learn Mem. 2000;73:87–93. doi: 10.1006/nlme.1999.3914. and erratum (2000) 74, 80–87. [DOI] [PubMed] [Google Scholar] · DOI
- [26]Todd P K, Mack K J. Brain Res Mol Brain Res. 2000;80:17–25. doi: 10.1016/s0169-328x(00)00098-x. [DOI] [PubMed] [Google Scholar] · DOI
- [27]Consortium D-B F X. Cell. 1994;78:23–33. [Google Scholar]
- [28]Irwin S A, Patel B, Idupulapati M, Harris J B, Cristostomo R, Larsen B P, Kooy F, Willems P J, Cras P, Kozlowski P B, et al. Am J Med Genet. 2001;98:161–167. doi: 10.1002/1096-8628(20010115)98:2<161::aid-ajmg1025>3.0.co;2-b. [DOI] [PubMed] [Google Scholar] · DOI
- [32]Reiss A L, Aylward E, Freund L S, Joshi P K, Bryan R N. Ann Neurol. 1991;29:26–32. doi: 10.1002/ana.410290107. [DOI] [PubMed] [Google Scholar] · DOI
- [33]Reiss A L, Lee J, Freund L. Neurology. 1994;44:1317–1324. doi: 10.1212/wnl.44.7.1317. [DOI] [PubMed] [Google Scholar] · DOI
- [34]Reyniers E, Martin J J, Cras P, Van Marck E, Handig I, Jorens H Z, Oostra B A, Kooy R F, Willems P J. Am J Med Genet. 1999;84:245–249. doi: 10.1002/(sici)1096-8628(19990528)84:3<245::aid-ajmg16>3.0.co;2-u. [DOI] [PubMed] [Google Scholar] · DOI
Cited by
Sorted by citations
BDNF function in adult synaptic plasticity: The synaptic consolidation hypothesis
Bramham, C. R., & Messaoudi, E. (2005) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2005.06.003 · Cited by 1,193 · see citing works
Zoghbi, H. Y., & Bear, M. F. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a009886 · Cited by 797 · see citing works
Zalfa, F., Giorgi, M., Primerano, B., Moro, A., Di Penta, A., Reis, S., Oostra, B., & Bagni, C. (2003) · Cell · doi:10.1016/s0092-8674(03)00079-5 · Cited by 676 · see citing works
From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome
Bagni, C., & Greenough, W. T. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1667 · Cited by 475 · see citing works
Self-citationBilousova, T. V., Dansie, L., Ngo, M., Aye, J., Charles, J. R., Ethell, D. W., & Ethell, I. M. (2009) · Journal of Medical Genetics · doi:10.1136/jmg.2008.061796 · Cited by 465 · see citing works
Belmonte, M. K., Cook, E. H., Anderson, G. M., Rubenstein, J. L. R., Greenough, W. T., Beckel-Mitchener, A., Courchesne, E., Boulanger, L. M., Powell, S. B., Levitt, P. R., et al. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001499 · Cited by 442 · see citing works
Self-citationSchenck, A., Bardoni, B., Langmann, C., Harden, N., Mandel, J.-L., & Giangrande, A. (2003) · Neuron · doi:10.1016/s0896-6273(03)00354-4 · Cited by 316 · see citing works
Restivo, L., Ferrari, F., Passino, E., Sgobio, C., Bock, J., Oostra, B. A., Bagni, C., & Ammassari-Teule, M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504984102 · Cited by 299 · see citing works
FMRP Mediates mGluR5-Dependent Translation of Amyloid Precursor Protein
Westmark, C. J., & Malter, J. S. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050052 · Cited by 292 · see citing works
“FMRP is required for type 1 metabotropic glutamate receptor (mGluR)–dependent translation of synaptic proteins, including FMRP and postsynaptic density 95 (PSD-95) [21,22].”
BackgroundInfluentialDarnell, J. C., Fraser, C. E., Mostovetsky, O., Stefani, G., Jones, T. A., Eddy, S. R., & Darnell, R. B. (2005) · Genes & Development · doi:10.1101/gad.1276805 · Cited by 287 · see citing works
Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice.
Frankland, P. W., Wang, Y., Rosner, B., Shimizu, T., Balleine, B. W., Dykens, E. M., Ornitz, E. M., & Silva, A. J. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001432 · Cited by 275 · see citing works
Functional anatomy of impaired selective attention and compensatory processing in autism
Belmonte, M. K., & Yurgelun-Todd, D. A. (2003) · Cognitive Brain Research · doi:10.1016/s0926-6410(03)00189-7 · Cited by 266 · see citing works
Nakamoto, M., Nalavadi, V., Epstein, M. P., Narayanan, U., Bassell, G. J., & Warren, S. T. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707484104 · Cited by 245 · see citing works
Henderson, C., Wijetunge, L., Kinoshita, M. N., Shumway, M., Hammond, R. S., Postma, F. R., Brynczka, C., Rush, R., Thomas, A., Paylor, R., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004218 · Cited by 249 · see citing works
Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse
Kazdoba, T. M., Leach, P. T., Silverman, J. L., & Crawley, J. N. (2014) · Intractable & Rare Diseases Research · doi:10.5582/irdr.2014.01024 · Cited by 241 · see citing works
Cytogenetic abnormalities and fragile-x syndrome in Autism Spectrum Disorder
Reddy, K. S. (2005) · BMC Medical Genetics · doi:10.1186/1471-2350-6-3 · Cited by 222 · see citing works
A phenotypic and molecular characterization of the <i>fmr1‐tm1Cgr</i> Fragile X mouse
Yan, Q. J., Asafo‐Adjei, P. K., Arnold, H. M., Brown, R. E., & Bauchwitz, R. P. (2004) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2004.00087.x · Cited by 213 · see citing works
Weiler, I. J., Spangler, C. C., Klintsova, A. Y., Grossman, A. W., Kim, S. H., Bertaina-Anglade, V., Khaliq, H., de Vries, F. E., Lambers, F. A. E., Hatia, F., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407533101 · Cited by 210 · see citing works
Self-citationCircuit and Plasticity Defects in the Developing Somatosensory Cortex of<i>Fmr1</i>Knock-Out Mice
Bureau, I., Shepherd, G. M. G., & Svoboda, K. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1076-08.2008 · Cited by 201 · see citing works
Fragile X: Leading the Way for Targeted Treatments in Autism
Wang, L. W., Berry-Kravis, E., & Hagerman, R. J. (2010) · Neurotherapeutics · doi:10.1016/j.nurt.2010.05.005 · Cited by 176 · see citing works
Khandjian, E. W., Huot, M.-E., Tremblay, S., Davidovic, L., Mazroui, R., & Bardoni, B. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405398101 · Cited by 178 · see citing works
Genetic-background modulation of core and variable autistic-like symptoms in Fmr1 knock-out mice
Pietropaolo, S., Guilleminot, A., Martin, B., D'Amato, F. R., & Crusio, W. E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017073 · Cited by 178 · see citing works
Psychopharmacology in fragile X syndrome—Present and future
Berry‐Kravis, E., & Potanos, K. (2004) · Mental Retardation and Developmental Disabilities Research Reviews · doi:10.1002/mrdd.20007 · Cited by 151 · see citing works
Larson, J., Jessen, R. E., Kim, D., Fine, A.-K. S., & du Hoffmann, J. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.2638-05.2005 · Cited by 135 · see citing works
Long-lasting effects of minocycline on behavior in young but not adult Fragile X mice.
Dansie, L. E., Phommahaxay, K., Okusanya, A. G., Uwadia, J., Huang, M., Rotschafer, S. E., Razak, K. A., Ethell, D. W., & Ethell, I. M. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.04.058 · Cited by 95 · see citing works
Van der Molen, M. J. W., Van der Molen, M. W., Ridderinkhof, K. R., Hamel, B. C. J., Curfs, L. M. G., & Ramakers, G. J. A. (2012) · Clinical Neurophysiology · doi:10.1016/j.clinph.2011.08.023 · Cited by 88 · see citing works
Modeling autism-relevant behavioral phenotypes in rats and mice: Do ‘autistic’ rodents exist?
Servadio, M., Vanderschuren, L. J. M. J., & Trezza, V. (2015) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000163 · Cited by 76 · see citing works
Brief Report: Acamprosate in Fragile X Syndrome
Erickson, C. A., Mullett, J. E., & McDougle, C. J. (2010) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-010-0988-9 · Cited by 67 · see citing works
Aberrant Brain Activation During Gaze Processing in Boys With Fragile X Syndrome
Watson, C., Hoeft, F., Garrett, A. S., Hall, S. S., & Reiss, A. L. (2008) · Archives of General Psychiatry · doi:10.1001/archpsyc.65.11.1315 · Cited by 65 · see citing works
Treatments for fragile X syndrome: A closer look at the data
Hall, S. S. (2009) · Developmental Disabilities Research Reviews · doi:10.1002/ddrr.78 · Cited by 56 · see citing works
Wang, H., Kim, S. S., & Zhuo, M. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.116293 · Cited by 52 · see citing works
de Esch, C. E. F., van den Berg, W. E., Buijsen, R. A. M., Jaafar, I. A., Nieuwenhuizen-Bakker, I. M., Gasparini, F., Kushner, S. A., & Willemsen, R. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.12.021 · Cited by 45 · see citing works
- Authors
- Greenough, W. T., Klintsova, A. Y., Irwin, S. A., Galvez, R., Bates, K. E., & Weiler, I. J.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-06-19
- Volume
- 98
- Issue
- 13
- Pages
- 7101-7106
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC34629
- OpenAlex
- W2026402282
- Cited by
- 317
- References
- 8
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 6 · 2020: 7 · 2019: 6 · 2018: 5 · 2017: 8 · 2016: 11 · 2015: 8 · 2014: 13 · 2013: 11 · 2012: 17
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01hd037175-03)
- National Institute on Aging (AG10154, R01AG010154)
- National Institute of Mental Health (MH-35321, R01MH035321, R37MH035321)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 37175)
- 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, dendritic spines, polysomes, synaptoneurosomes, metabotropic glutamate receptors, synaptogenesis, RNA-binding proteins
- MeSH terms
- Animals, Brain, Dendrites, Fragile X Syndrome, Gene Expression Regulation, Humans, Intellectual Disability, Nerve Tissue Proteins, Neurons, Polyribosomes, RNA, Messenger, Synapses, RNA-Binding Proteins, Receptors, Metabotropic Glutamate, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
