The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.
Correction of Fragile X Syndrome in Mice
Open accessAbstract
Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders.
Overview
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
Verification
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Moreover, several forms of NMDA-receptor-dependent plasticity are impaired by loss of FMRP. LTP is abolished in cortex and amygdala (but not hippocampus), the threshold for spike-timing dependent plasticity is increased, and ocular dominance plasticity is altered (Desai et al., 2006; Dolen et al., 2007; Li et al., 2002; Meredith et al., 2007; Zhao et al., 2005).”
From Regulation of Synaptic Structure and Function by FMRP-Associated MicroRNAs miR-125b and miR-132 (2010) · cites this paper as Dolen et al., 2007
Experimental — accuracy not yet measuredIn the citing paper
“A 50% reduction in mGluR5 expression decreased excess translation and improved behavior in the fragile X mouse model 42 .”
From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [42]
In the citing paper
“A similar suppressor effect has been demonstrated by the decrease of abnormal behavior of the Fmr1 mutant mice carrying a heterozygous mutation of the metabotropic glutamate receptor mGluR5 [84].”
From Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders (2012) · cites this paper as [84]
In 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 [58]
In the citing paper
“Fmr1 mutant mice have a significant delay in the stabilization of dendritic spines and in the maturation of thalamocortical and corticocortical synapses 94-98 , defects associated with a temporal shift in the critical period for sensory-induced plasticity across different cortical areas 94,97,99-101 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [99]
In the citing paper
“Preclinical studies have primarily focused on mGluR5 signaling as potential targets for treatment in adult mice 99,110-113 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [99]
In the citing paper
“Genetic reduction of mGluR5 activity achieves correction of multiple phenotypes in Fmr1-KO mice and dfmr1−/− flies26.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [26]
In the citing paper
“One striking conclusion of the broad array of preclinical studies is that these core deficits can be consistently rescued by more than ten genetic approaches and multiple classes of pharmacological compounds including mGluR antagonists (MPEP, fenobam, mavoglurant and CTEP), GABA agonists, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), mechanistic target of rapamycin (mTOR) inhib”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [26]
In the citing paper
“This study demonstrates in the fragile X mouse model the rescue of a range of phenotypes relevant to the human disorder by reducing mGluR5 expression.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [26]
In the citing paper
“The resulting 50% reduction in mGluR5 protein levels in the offspring led to the correction of typical FXS phenotypic features, including spine dysmorphogenesis and audiogenic seizures, and restored mGluR-LTD (90).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [90]
In the citing paper
“Discovery of elevated metabotropic glutamate receptor subtype 5 (mGluR5)–mediated signaling and protein synthesis in fragile X knockout mice (53–56) provided the rationale for testing mGluR5 antagonists in ongoing fragile X clinical trials.”
From Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism (2012) · cites this paper as [54]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Learning induces long-term potentiation in the hippocampus
Whitlock, J. R., Heynen, A. J., Shuler, M. G., & Bear, M. F. (2006) · Science · doi:10.1126/science.1128134 · Cited by 1,913
Self-citationThe 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-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
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
Fmr1 knockout mice: A model to study fragile X mental retardation
THEDUTCHBELGIANFRAGILEXCONSOR (1994) · Cell · doi:10.1016/0092-8674(94)90569-x · Cited by 1,108
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-citationLu, Y.-M., Jia, Z., Janus, C., Henderson, J. T., Gerlai, R., Wojtowicz, J. M., & Roder, J. C. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-13-05196.1997 · Cited by 634
(1994) · PubMed · Cited by 565
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
McBride, 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 484
Flagged first, then by citations
Cited by
Sorted by citations
Items 101–139 of 139
Haploinsufficiency of Cyfip1 Produces Fragile X-Like Phenotypes in Mice
Bozdagi, O., Sakurai, T., Dorr, N., Pilorge, M., Takahashi, N., & Buxbaum, J. D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042422 · Cited by 97
Cellular and synaptic network defects in autism
Peça, J., & Feng, G. (2012) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2012.02.015 · Cited by 96
Padmashri, R., Reiner, B. C., Suresh, A., Spartz, E., & Dunaevsky, A. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.2514-13.2013 · Cited by 96
FMR1 premutation and full mutation molecular mechanisms related to autism
Hagerman, R., Au, J., & Hagerman, P. (2011) · Journal of Neurodevelopmental Disorders · doi:10.1007/s11689-011-9084-5 · Cited by 85
Fatemi, S. H., & Folsom, T. D. (2011) · Molecular Autism · doi:10.1186/2040-2392-2-6 · Cited by 84
Convergence of Hippocampal Pathophysiology in Syngap +/− and Fmr1 −/ y Mice
Barnes, S. A., Wijetunge, L. S., Jackson, A. D., Katsanevaki, D., Osterweil, E. K., Komiyama, N. H., Grant, S. G. N., Bear, M. F., Nägerl, U. V., Kind, P. C., et al. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.1087-15.2015 · Cited by 84
Self-citationSawicka, K., Pyronneau, A., Chao, M., Bennett, M. V. L., & Zukin, R. S. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1610812113 · Cited by 84
Resilience against predator stress and dendritic morphology of amygdala neurons
Mitra, R., Adamec, R., & Sapolsky, R. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.08.014 · Cited by 80
The role of fragile X mental retardation protein in major mental disorders
Fatemi, S. H., & Folsom, T. D. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.11.011 · Cited by 80
Asiminas, A., Jackson, A. D., Louros, S. R., Till, S. M., Spano, T., Dando, O., Bear, M. F., Chattarji, S., Hardingham, G. E., Osterweil, E. K., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aao0498 · Cited by 78
Self-citationSu, T., Fan, H.-X., Jiang, T., Sun, W.-W., Den, W.-Y., Gao, M.-M., Chen, S.-Q., Zhao, Q.-H., & Yi, Y.-H. (2011) · Psychopharmacology · doi:10.1007/s00213-010-2130-2 · Cited by 76
Gross, C., Raj, N., Molinaro, G., Allen, A. G., Whyte, A. J., Gibson, J. R., Huber, K. M., Gourley, S. L., & Bassell, G. J. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.03.065 · Cited by 71
Early life stress inhibits expression of a novel innate immune pathway in the developing hippocampus
Wei, L., Simen, A., Mane, S., & Kaffman, A. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.239 · Cited by 71
Parallel social information processing circuits are differentially impacted in autism
Lewis, E. M., Stein-O’Brien, G. L., Patino, A. V., Nardou, R., Grossman, C. D., Brown, M., Bangamwabo, B., Ndiaye, N., Giovinazzo, D., Dardani, I., et al. (2020) · Neuron · doi:10.1016/j.neuron.2020.10.002 · Cited by 72
Self-citationBrief 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
Michalon, A., Bruns, A., Risterucci, C., Honer, M., Ballard, T. M., Ozmen, L., Jaeschke, G., Wettstein, J. G., von Kienlin, M., Künnecke, B., et al. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.05.038 · Cited by 67
Reversibility of functional deficits in experimental models of Rett syndrome
Cobb, S., Guy, J., & Bird, A. (2010) · Biochemical Society Transactions · doi:10.1042/bst0380498 · Cited by 67
Oxytocin: Parallel Processing in the Social Brain?
Dölen, G. (2015) · Journal of Neuroendocrinology · doi:10.1111/jne.12284 · Cited by 65
Self-citationJaeschke, G., Kolczewski, S., Spooren, W., Vieira, E., Bitter-Stoll, N., Boissin, P., Borroni, E., Büttelmann, B., Ceccarelli, S., Clemann, N., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/jm501642c · Cited by 66
Radwan, B., Dvorak, D., & Fenton, A. A. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.01.003 · Cited by 63
Kiser, D. P., Rivero, O., & Lesch, K. (2015) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.12392 · Cited by 58
Current perspectives in autism spectrum disorder: from genes to therapy
Chahrour, M., O'Roak, B. J., Santini, E., Samaco, R. C., Kleiman, R. J., & Manzini, M. C. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.2335-16.2016 · Cited by 54
Mechanisms Underlying Circuit Dysfunction in Neurodevelopmental Disorders
Exposito-Alonso, D., & Rico, B. (2022) · Annual Review of Genetics · doi:10.1146/annurev-genet-072820-023642 · Cited by 49
De Rubeis, S., Fernández, E., Buzzi, A., Di Marino, D., & Bagni, C. (2012) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-7091-0932-8_23 · Cited by 48
Choi, C. H., Schoenfeld, B. P., Bell, A. J., Hinchey, J., Rosenfelt, C., Gertner, M. J., Campbell, S. R., Emerson, D., Hinchey, P., Kollaros, M., et al. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00136 · Cited by 46
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
Heads‐up: New roles for the fragile X mental retardation protein in neural stem and progenitor cells
Callan, M. A., & Zarnescu, D. C. (2011) · genesis · doi:10.1002/dvg.20745 · Cited by 39
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
Boda, B., Mendez, P., Boury‐Jamot, B., Magara, F., & Muller, D. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12488 · Cited by 30
Lovastatin, Not Simvastatin, Corrects Core Phenotypes in the Fragile X Mouse Model
Muscas, M., Louros, S. R., & Osterweil, E. K. (2019) · eneuro · doi:10.1523/eneuro.0097-19.2019 · Cited by 30
Self-citationStem cells and modeling of autism spectrum disorders
Freitas, B. C. G., Trujillo, C. A., Carromeu, C., Yusupova, M., Herai, R. H., & Muotri, A. R. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2012.09.017 · Cited by 27
Normal Performance of Fmr1 Mice on a Touchscreen Delayed Nonmatching to Position Working Memory Task
Leach, P. T., Hayes, J., Pride, M., Silverman, J. L., & Crawley, J. N. (2016) · eneuro · doi:10.1523/eneuro.0143-15.2016 · Cited by 27
Siegel, J. J., Chitwood, R. A., Ding, J. M., Payne, C., Taylor, W., Gray, R., Zemelman, B. V., & Johnston, D. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.0571-17.2017 · Cited by 27
Quantitative Profiling of Brain Lipid Raft Proteome in a Mouse Model of Fragile X Syndrome
Kalinowska, M., Castillo, C., & Francesconi, A. (2015) · PLOS ONE · doi:10.1371/journal.pone.0121464 · Cited by 26
Enhanced Operant Extinction and Prefrontal Excitability in a Mouse Model of Angelman Syndrome
Sidorov, M. S., Judson, M. C., Kim, H., Rougie, M., Ferrer, A. I., Nikolova, V. D., Riddick, N. V., Moy, S. S., & Philpot, B. D. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.2828-17.2018 · Cited by 25
New therapeutic options for autism spectrum disorder: experimental evidences
Peñagarikano, O. (2015) · Experimental Neurobiology · doi:10.5607/en.2015.24.4.301 · Cited by 24
Careaga, M., Noyon, T., Basuta, K., Van de Water, J., Tassone, F., Hagerman, R. J., & Ashwood, P. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-110 · Cited by 20
Rethinking intellectual disability from neuro- to astro-pathology.
Fernández-Blanco, Á., & Dierssen, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239039 · Cited by 19
Janz, P., Bainier, M., Marashli, S., Gross, S., & Redondo, R. L. (2025) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110182 · Cited by 11
Metadata
- Authors
- Dölen, G., Osterweil, E., Rao, B. S. S., Smith, G. B., Auerbach, B. D., Chattarji, S., & Bear, M. F.
- Affiliations
- Howard Hughes Medical Institute (US)
- National Institute of Mental Health and Neurosciences (IN)
- Tata Institute of Fundamental Research (IN)
- Corresponding author
- Bear, Mark F.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2007-12
- Volume
- 56
- Issue
- 6
- Pages
- 955-962
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2199268
- OpenAlex
- W2084889756
- Cited by
- 979
- References
- 39
- Citations by year
- 2026: 19 · 2025: 26 · 2024: 19 · 2023: 26 · 2022: 30 · 2021: 42 · 2020: 44 · 2019: 41 · 2018: 35 · 2017: 57 · 2016: 62 · 2015: 73 · 2014: 65 · 2013: 81 · 2012: 87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2055 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Simons Foundation
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- National Institute of Mental Health
- FRAXA Research Foundation
- 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, FMRP, FMR1 gene silencing, mGluR5, metabotropic glutamate receptors, autism spectrum disorder, intellectual disability, pathogenesis, therapeutic target
- MeSH terms
- Acoustic Stimulation, Animals, Behavior, Animal, Disease Models, Animal, Fragile X Syndrome, Gene Expression Regulation, Heterozygote, Functional Laterality, Learning, Mice, Inbred C57BL, Neuronal Plasticity, Neurons, Phenotype, Seizures, Visual Cortex, Multivariate Analysis, Receptors, Metabotropic Glutamate, Mice, Knockout, Mice, Fragile X Messenger Ribonucleoprotein 1, 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
