Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors
Open accessAbstract
Fragile X syndrome (FXS), a common inherited form of mental retardation, is caused by the functional absence of the fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates the translation of specific mRNAs at synapses. Altered synaptic plasticity has been described in a mouse FXS model. However, the mechanism by which the loss of FMRP alters synaptic function, and subsequently causes the mental impairment, is unknown. Here, in cultured hippocampal neurons, we used siRNAs against Fmr1 to demonstrate that a reduction of FMRP in dendrites leads to an increase in internalization of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit, GluR1, in dendrites. This abnormal AMPAR trafficking was caused by spontaneous action potential-driven network activity without synaptic stimulation by an exogenous agonist and was rescued by 2-methyl-6-phenylethynyl-pyridine (MPEP), an mGluR5-specific inverse agonist. Because AMPAR internalization depends on local protein synthesis after mGluR5 stimulation, FMRP, a negative regulator of translation, may be viewed as a counterbalancing signal, wherein the absence of FMRP leads to an apparent excess of mGluR5 signaling in dendrites. Because AMPAR trafficking is a driving process for synaptic plasticity underlying learning and memory, our data suggest that hypersensitive AMPAR internalization in response to excess mGluR signaling may represent a principal cellular defect in FXS, which may be corrected by using mGluR antagonists.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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 activity is regulated in response to metabotropic glutamate receptors, AMPA receptors, GABA receptors, NMDA receptors, and TrkB receptors.
“FMRP activity is regulated in response to metabotropic glutamate receptors (mGluRs) (78), 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptors (79), γ-aminobutyric acid (GABA) receptors (76,80,81), N-methyl-d-aspartate (NMDA) receptors (82)(83)(84), and the tyrosine kinase or BDNF/NT-3 growth factor (TrkB) receptors (85).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [79]
Elevated long-term depression causes loss of AMPA and NMDA receptors from the surface of postsynaptic structures, possibly affecting elongation of dendritic spines.
“Elevated LTD causes loss of AMPA and NMDA receptors from the surface of postsynaptic structures, possibly affecting the elongation of dendritic spines (75,79).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [79]
Cites
Malenka, R. C., & Bear, M. F. (2004) · Neuron · doi:10.1016/j.neuron.2004.09.012 · Cited by 3,968 · see citing works
Asymmetry in the Assembly of the RNAi Enzyme Complex
Schwarz, D. S., Hutvágner, G., Du, T., Xu, Z., Aronin, N., & Zamore, P. D. (2003) · Cell · doi:10.1016/s0092-8674(03)00759-1 · Cited by 2,323 · see citing works
Ruppert, D., WAND, M. P., & Carroll, R. J. (2003) · Cambridge University Press eBooks · doi:10.1017/cbo9780511755453 · Cited by 2,153 · see citing works
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 · see citing works
Self-citationAltered 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 · see citing works
Self-citationBanker, G. A., & Goslin, K. (1998) · Cited by 1,290 · see citing works
AMPA receptor trafficking at excitatory synapses
Bredt, D. S., & Nicoll, R. A. (2003) · Neuron · doi:10.1016/s0896-6273(03)00640-8 · Cited by 1,150 · see citing works
Reinsertion or Degradation of AMPA Receptors Determined by Activity-Dependent Endocytic Sorting
Ehlers, M. D. (2000) · Neuron · doi:10.1016/s0896-6273(00)00129-x · Cited by 1,096 · see citing works
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 · see citing works
Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD
Beattie, E. C., Carroll, R. C., Yu, X., Morishita, W., Yasuda, H., von Zastrow, M., & Malenka, R. C. (2000) · Nature Neuroscience · doi:10.1038/81823 · Cited by 745 · see citing works
Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization
Lin, J., Ju, W. H., Foster, K. A., Lee, S. H., Ahmadian, G., Wyszynski, M. W., Wang, Y. T., & Sheng, M. (2000) · Nature Neuroscience · doi:10.1038/81814 · Cited by 557 · see citing works
Internalization of ionotropic glutamate receptors in response to mGluR activation
Snyder, E. M., Philpot, B. D., Huber, K. M., Dong, X., Fallon, J. R., & Bear, M. F. (2001) · Nature Neuroscience · doi:10.1038/nn746 · Cited by 539 · see citing works
Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP
Yan, Q. J., Rammal, M., Tranfaglia, M., & Bauchwitz, R. P. (2005) · Neuropharmacology · doi:10.1016/j.neuropharm.2005.06.004 · Cited by 521 · see citing works
A Decade of Molecular Studies of Fragile X Syndrome
O'Donnell, W. T., & Warren, S. T. (2002) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.25.112701.142909 · Cited by 481 · see citing works
Self-citationMcBride, S. M. J., Choi, C. H., Wang, Y., Liebelt, D. A., Braunstein, E. M., Ferreiro, D., Sehgal, A., Siwicki, K. K., Dockendorff, T. C., Nguyen, H. T., et al. (2005) · Neuron · doi:10.1016/j.neuron.2005.01.038 · Cited by 473 · see citing works
Hou, L., Antion, M. D., Hu, D., Spencer, C. M., Paylor, R., & Klann, E. (2006) · Neuron · doi:10.1016/j.neuron.2006.07.005 · Cited by 469 · see citing works
Role of ampa receptor endocytosis in synaptic plasticity
Carroll, R. C., Beattie, E. C., von Zastrow, M., & Malenka, R. C. (2001) · Nature Reviews Neuroscience · doi:10.1038/35072500 · Cited by 448 · see citing works
Dynamin-dependent endocytosis of ionotropic glutamate receptors
Carroll, R. C., Beattie, E. C., Xia, H., Lüscher, C., Altschuler, Y., Nicoll, R. A., Malenka, R. C., & von Zastrow, M. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.24.14112 · Cited by 421 · see citing works
Koekkoek, S. K. E., Yamaguchi, K., Milojkovic, B. A., Dortland, B. R., Ruigrok, T. J. H., Maex, R., Graaf, W. D., Smit, A. E., VanderWerf, F., Bakker, C. E., et al. (2005) · Neuron · doi:10.1016/j.neuron.2005.07.005 · Cited by 417 · see citing works
Akaike, H. (1985) · Springer eBooks · doi:10.1007/978-1-4613-8560-8_1 · Cited by 373 · see citing works
Rat Hippocampal Neurons in Low-Density Culture
Goslin, K., Asmussen, H., & Banker, G. A. (1998) · The MIT Press eBooks · doi:10.7551/mitpress/4913.003.0020 · Cited by 364 · see citing works
Antar, L. N., Afroz, R., Dictenberg, J. B., Carroll, R. C., & Bassell, G. J. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.0099-04.2004 · Cited by 360 · see citing works
Self-citationSynaptic Plasticity and AMPA Receptor Trafficking
Malenka, R. C. (2003) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1300.001 · Cited by 324 · see citing works
Synaptic regulation of protein synthesis and the fragile X protein
Greenough, W. T., Klintsova, A. Y., Irwin, S. A., Galvez, R., Bates, K. E., & Weiler, I. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141145998 · Cited by 317 · see citing works
Nosyreva, E. D., & Huber, K. M. (2006) · Journal of Neurophysiology · doi:10.1152/jn.01316.2005 · Cited by 292 · see citing works
Li, J., Pelletier, M. R., Perez-Velazquez, J. L., & Carlen, P. L. (2002) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.2001.1085 · Cited by 268 · see citing works
Antar, L. N., Dictenberg, J. B., Plociniak, M., Afroz, R., & Bassell, G. J. (2005) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2005.00128.x · Cited by 246 · see citing works
Self-citationDecreased hippocampal expression of a glutamate receptor gene in schizophrenia
Harrison, P. J., McLaughlin, D. P., & Kerwin, R. W. (1991) · The Lancet · doi:10.1016/0140-6736(91)93392-m · Cited by 240 · see citing works
AMPA receptor downscaling at the onset of Alzheimer's disease pathology in double knockin mice
Chang, E. H., Savage, M. J., Flood, D. G., Thomas, J. M., Levy, R. B., Mahadomrongkul, V., Shirao, T., Aoki, C., & Huerta, P. T. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507313103 · Cited by 225 · see citing works
Atkinson, A. C., & Fienberg, S. E. (1985) · Springer eBooks · doi:10.1007/978-1-4613-8560-8 · Cited by 217 · see citing works
Chuang, S.-C., Zhao, W., Bauchwitz, R., Yan, Q., Bianchi, R., & Wong, R. K. S. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.1777-05.2005 · Cited by 190 · see citing works
BAY36-7620: A Potent Non-Competitive mGlu1 Receptor Antagonist with Inverse Agonist Activity.
Carroll, F. Y., Stolle, A., Beart, P. M., Voerste, A. A. W., Brabet, I., Mauler, F., Joly, C., Antonicek, H., Bockaert, J., Müller, T. M., et al. (2001) · Molecular Pharmacology · doi:10.1124/mol.59.5.965 · Cited by 171 · see citing works
Metabotropic glutamate receptor activation causes a rapid redistribution of AMPA receptors
Xiao, M., Zhou, Q., & Nicoll, R. A. (2001) · Neuropharmacology · doi:10.1016/s0028-3908(01)00134-4 · Cited by 169 · see citing works
Pfeiffer, B. E., & Huber, K. M. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.0054-07.2007 · Cited by 154 · see citing works
Volk, L. J., Daly, C. A., & Huber, K. M. (2006) · Journal of Neurophysiology · doi:10.1152/jn.00383.2005 · Cited by 150 · see citing works
Transcription, translation and fragile X syndrome
Garber, K. B., Smith, K. T., Reines, D., & Warren, S. T. (2006) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2006.04.010 · Cited by 147 · see citing works
Self-citationTucker, B., Richards, R. I., & Lardelli, M. T. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl422 · Cited by 133 · see citing works
Giuffrida, R., Musumeci, S., D'Antoni, S., Bonaccorso, C. M., Giuffrida-Stella, A. M., Oostra, B. A., & Catania, M. V. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.0932-05.2005 · Cited by 119 · see citing works
Antar, L. N., & Bassell, G. J. (2003) · Neuron · doi:10.1016/s0896-6273(03)00090-4 · Cited by 117 · see citing works
Self-citationCataract extraction in high myopic eyes.
Ku, W., Chuang, L., & Lai, C. (2002) · PubMed · Cited by 24 · see citing works
Craig, A. M. (1998) · The MIT Press eBooks · doi:10.7551/mitpress/4913.003.0009 · Cited by 16 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Fragile X Syndrome: Loss of Local mRNA Regulation Alters Synaptic Development and Function
Bassell, G. J., & Warren, S. T. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.004 · Cited by 1,051 · see citing works
Self-citationThe Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc
Greer, P. L., Hanayama, R., Bloodgood, B. L., Mardinly, A. R., Lipton, D. M., Flavell, S. W., Kim, T.-K., Griffith, E. C., Waldon, Z., Maehr, R., et al. (2010) · Cell · doi:10.1016/j.cell.2010.01.026 · Cited by 30 · see citing works
A pilot open label, single dose trial of fenobam in adults with fragile X syndrome
Berry-Kravis, E., Hessl, D., Coffey, S., Hervey, C., Schneider, A., Yuhas, J., Hutchison, J., Snape, M., Tranfaglia, M., Nguyen, D. V., et al. (2009) · Journal of Medical Genetics · doi:10.1136/jmg.2008.063701 · Cited by 411 · see citing works
Failure of neuronal homeostasis results in common neuropsychiatric phenotypes
Ramocki, M. B., & Zoghbi, H. Y. (2008) · Nature · doi:10.1038/nature07457 · Cited by 399 · see citing works
Osterweil, E. K., Krueger, D. D., Reinhold, K., & Bear, M. F. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.3888-10.2010 · Cited by 384 · see citing works
The Pathophysiology of Fragile X (and What It Teaches Us about Synapses)
Bhakar, A. L., Dölen, G., & Bear, M. F. (2012) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-060909-153138 · Cited by 370 · see citing works
Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics
Bagni, C., Tassone, F., Neri, G., & Hagerman, R. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63141 · Cited by 321 · see citing works
Delayed Stabilization of Dendritic Spines in Fragile X Mice
Cruz-Martin, A., Crespo, M., & Portera-Cailliau, C. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0577-10.2010 · Cited by 321 · see citing works
Toward Fulfilling the Promise of Molecular Medicine in Fragile X Syndrome
Krueger, D. D., & Bear, M. F. (2011) · Annual Review of Medicine · doi:10.1146/annurev-med-061109-134644 · Cited by 259 · 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
Self-citationSocial approach in genetically engineered mouse lines relevant to autism
Moy, S. S., Nadler, J. J., Young, N. B., Nonneman, R. J., Grossman, A. W., Murphy, D. L., D’Ercole, A. J., Crawley, J. N., Magnuson, T. R., & Lauder, J. M. (2009) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2008.00452.x · Cited by 246 · see citing works
Gross, C., Nakamoto, M., Yao, X., Chan, C.-B., Yim, S. Y., Ye, K., Warren, S. T., & Bassell, G. J. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.0402-10.2010 · Cited by 241 · see citing works
Self-citationModeling 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
An epigenetic framework for neurodevelopmental disorders: From pathogenesis to potential therapy
Millan, M. J. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.11.015 · Cited by 229 · see citing works
Metabotropic Glutamate Receptor-Mediated Long-Term Depression: Molecular Mechanisms
Gladding, C. M., Fitzjohn, S. M., & Molnár, E. (2009) · Pharmacological Reviews · doi:10.1124/pr.109.001735 · Cited by 233 · see citing works
Narayanan, U., Nalavadi, V., Nakamoto, M., Thomas, G., Ceman, S., Bassell, G. J., & Warren, S. T. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.c800055200 · Cited by 216 · see citing works
Self-citationGenetics of intellectual disability
Ropers, H. H. (2008) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2008.07.008 · Cited by 199 · 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
The genetics of child psychiatric disorders: focus on autism and Tourette syndrome
State, M. W. (2010) · Neuron · doi:10.1016/j.neuron.2010.10.004 · Cited by 162 · see citing works
Gross, C., Yao, X., Pong, D. L., Jeromin, A., & Bassell, G. J. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6661-10.2011 · Cited by 161 · see citing works
Self-citationMcLennan, Y., Polussa, J., Tassone, F., & Hagerman, R. (2011) · Current Genomics · doi:10.2174/138920211795677886 · Cited by 160 · see citing works
Myrick, L. K., Deng, P.-Y., Hashimoto, H., Oh, Y. M., Cho, Y., Poidevin, M. J., Suhl, J. A., Visootsak, J., Cavalli, V., Jin, P., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1423094112 · Cited by 133 · see citing works
Self-citationNew perspectives on the biology of fragile X syndrome
Wang, T., Bray, S. M., & Warren, S. T. (2012) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2012.02.002 · Cited by 116 · see citing works
Self-citationCYFIP family proteins between autism and intellectual disability: links with Fragile X syndrome
Abekhoukh, S., & Bardoni, B. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00081 · Cited by 110 · see citing works
Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back
Gross, C., Hoffmann, A., Bassell, G. J., & Berry-Kravis, E. M. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0355-9 · Cited by 105 · see citing works
Self-citationGlutamate receptor dysfunction and drug targets across models of autism spectrum disorders
Carlson, G. C. (2012) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.02.003 · Cited by 102 · see citing works
<i>Sapap3</i> Deletion Causes mGluR5-Dependent Silencing of AMPAR Synapses
Wan, Y., Feng, G., & Calakos, N. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.2533-11.2011 · Cited by 101 · see citing works
Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice
Gantois, I., Pop, A. S., de Esch, C. E. F., Buijsen, R. A. M., Pooters, T., Gomez-Mancilla, B., Gasparini, F., Oostra, B. A., D’Hooge, R., & Willemsen, R. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.10.059 · Cited by 100 · see citing works
The neurochemical basis for the treatment of autism spectrum disorders and Fragile X syndrome
Hampson, D. R., Adusei, D. C., & Pacey, L. K. K. (2011) · Biochemical Pharmacology · doi:10.1016/j.bcp.2011.02.005 · Cited by 34 · see citing works
- Authors
- Nakamoto, M., Nalavadi, V., Epstein, M. P., Narayanan, U., Bassell, G. J., & Warren, S. T.
- Affiliations
- Departments of *Human Genetics,
- Cell Biology,
- Emory University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-09-25
- Volume
- 104
- Issue
- 39
- Pages
- 15537-15542
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2000537
- OpenAlex
- W1998232402
- Cited by
- 245
- References
- 41
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 4 · 2023: 7 · 2022: 8 · 2021: 8 · 2020: 8 · 2019: 11 · 2018: 8 · 2017: 7 · 2016: 13 · 2015: 20 · 2014: 18 · 2013: 16 · 2012: 17
- FWCI
- 11.65
- 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 Institute of Neurological Disorders and Stroke (NS-051127, R01NS051127)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 20521, HD 24064, R01HD020521, P30HD024064, R37HD020521)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- fragile X syndrome, FMRP, mGluR5, AMPA receptor internalization, GluR1, synaptic plasticity, local protein synthesis, translational regulation, MPEP, hippocampal neurons, mGluR antagonists, intellectual disability
- MeSH terms
- Animals, Disease Models, Animal, Fragile X Syndrome, Gene Expression Regulation, Hippocampus, Intellectual Disability, Neurons, RNA, Messenger, Receptors, AMPA, Receptors, Metabotropic Glutamate, Microscopy, Confocal, RNA, Small Interfering, Rats, Fragile X Messenger Ribonucleoprotein 1, Fragile X Mental Retardation Protein, Receptor, Metabotropic Glutamate 5
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
