Dysregulation of mTOR signaling in fragile X syndrome
Open accessAbstract
Fragile X syndrome, the most common form of inherited mental retardation and leading genetic cause of autism, is caused by transcriptional silencing of the Fmr1 gene. The fragile X mental retardation protein (FMRP), the gene product of Fmr1, is an RNA binding protein that negatively regulates translation in neurons. The Fmr1 knock-out mouse, a model of fragile X syndrome, exhibits cognitive deficits and exaggerated metabotropic glutamate receptor (mGluR)-dependent long-term depression at CA1 synapses. However, the molecular mechanisms that link loss of function of FMRP to aberrant synaptic plasticity remain unclear. The mammalian target of rapamycin (mTOR) signaling cascade controls initiation of cap-dependent translation and is under control of mGluRs. Here we show that mTOR phosphorylation and activity are elevated in hippocampus of juvenile Fmr1 knock-out mice by four functional readouts: (1) association of mTOR with regulatory associated protein of mTOR; (2) mTOR kinase activity; (3) phosphorylation of mTOR downstream targets S6 kinase and 4E-binding protein; and (4) formation of eukaryotic initiation factor complex 4F, a critical first step in cap-dependent translation. Consistent with this, mGluR long-term depression at CA1 synapses of FMRP-deficient mice is exaggerated and rapamycin insensitive. We further show that the p110 subunit of the upstream kinase phosphatidylinositol 3-kinase (PI3K) and its upstream activator PI3K enhancer PIKE, predicted targets of FMRP, are upregulated in knock-out mice. Elevated mTOR signaling may provide a functional link between overactivation of group I mGluRs and aberrant synaptic plasticity in the fragile X mouse, mechanisms relevant to impaired cognition in fragile X syndrome.
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In animal models of autism spectrum disorder, altered mTORC1 signaling contributes to synaptic dysfunction and aberrant network connectivity.
“Additionally in animal models of autism spectrum disorder (ASD), altered mTORC1 signaling contributes to the observed synaptic dysfunction and aberrant network connectivity (13,15,(21)(22)(23)(24)(25)(26)(27).”
From Analysis of proteins that rapidly change upon mechanistic/mammalian target of rapamycin complex 1 (mTORC1) repression identifies parkinson protein 7 (PARK7) as a novel protein aberrantly expressed in tuberous sclerosis complex (TSC) (2016) · cites this paper as [13]
The Introduction (page not provided) links elevated mTOR signaling in Fmr1 knockout mice to exaggerated synaptic long-term depression; the Discussion identifies fragile X syndrome as a genetic cause of autism. This supports the synaptic-dysfunction part of the claim in one relevant animal model, but the paper does not report aberrant network connectivity or establish the claim across ASD animal models generally. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe mTor pathway is enhanced in Fmr1-knockout neurons.
“Conversely, it was reported that the mTor pathway is enhanced in Fmr1-knockout neurons (Sharma et al., 2010; Sawicka et al., 2016).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Sharma et al., 2010
The Results report increased basal mTOR signaling in the hippocampus of Fmr1-knockout mice, supported by kinase activity and mTOR–raptor association. The claim is broader than that finding: the Results also report no difference in cortical mTOR phosphorylation between knockout and wild-type mice, so the source does not establish enhancement in knockout neurons generally. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCYFIP1 has a positive role in pS6-mediated translational regulation, opposite to FMRP.
“This finding shows a positive role for CYFIP1 in pS6-mediated translational regulation, which is an opposite function with respect to FMRP (Sharma et al., 2010; Maurin et al., 2014).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Sharma et al., 2010
The mTor pathway alteration in Fmr1-knockout neurons is not due to altered expression of mTor but rather to overactivation of PI3K because of overexpression of the catalytic PI3K subunit p110β.
“This alteration is not due to an altered expression of mTor (Sharma et al., 2010), but rather to the overactivation of PI3K, because of the overexpression of the catalytic PI3K subunit p110β (Gross et al., 2010; Gross and Bassell, 2012).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Sharma et al., 2010
PI3K is regulated by FMRP, is elevated in FXS mouse knockouts, and downregulation of this pathway has been shown to have therapeutic effect in ASD and FXS mouse models.
“PI3K, which is regulated by FMRP,59 is elevated in FXS mouse knockouts,62,63 and downregulation of this pathway has been shown to have therapeutic effect in ASD and FXS mouse models.”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [63]
Enhanced mTOR signaling and cap-dependent translation initiation complex are found also in mouse models of human Fragile X Syndrome, characterized by the lack of FMRP.
“Enhanced mTOR signaling and cap-dependent translation initiation complex are found also in mouse models of human Fragile X Syndrome, characterized by the lack of FMRP.85, 86, 87”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [85]
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Cites
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216 · see citing works
Upstream and downstream of mTOR
Hay, N., & Sonenberg, N. (2004) · Genes & Development · doi:10.1101/gad.1212704 · Cited by 4,181 · see citing works
Kim, D.-H., Sarbassov, D., Ali, S. M., King, J. E., Latek, R., Erdjument-Bromage, H., Tempst, P., & Sabatini, D. (2002) · Cell · doi:10.1016/s0092-8674(02)00808-5 · Cited by 3,135 · see citing works
PHARMACOLOGY AND FUNCTIONS OF METABOTROPIC GLUTAMATE RECEPTORS
Conn, P. J., & Pin, J. (1997) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.37.1.205 · Cited by 3,083 · see citing works
The metabotropic glutamate receptors: Structure and functions
Pin, J., & Duvoisin, R. M. (1995) · Neuropharmacology · doi:10.1016/0028-3908(94)00129-g · Cited by 2,267 · see citing works
Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action.
Hara, K., Maruki, Y., Long, S., Yoshino, K., Oshiro, N., Hidayat, S., Tokunaga, C., Avruch, J., & Yonezawa, K. (2002) · Cell · doi:10.1016/s0092-8674(02)00833-4 · Cited by 1,916 · see citing works
Growing roles for the mTOR pathway
Sarbassov, D. D., Ali, S. M., & Sabatini, D. M. (2005) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2005.09.009 · Cited by 1,556 · see citing works
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 · see citing works
mTOR and cancer: insights into a complex relationship
Sabatini, D. M. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1974 · Cited by 1,322 · see citing works
Targeting the PI3K-Akt pathway in human cancer
Luo, J., Manning, B. D., & Cantley, L. C. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00248-4 · Cited by 1,290 · see citing works
Brown, 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 · 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 1,013 · see citing works
Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia
Emamian, E. S., Hall, D., Birnbaum, M. J., Karayiorgou, M., & Gogos, J. A. (2004) · Nature Genetics · doi:10.1038/ng1296 · Cited by 914 · see citing works
Butler, M. G., Dasouki, M. J., Zhou, X.-P., Talebizadeh, Z., Brown, M., Takahashi, T. N., Miles, J. H., Wang, C. H., Stratton, R., Pilarski, R., et al. (2005) · Journal of Medical Genetics · doi:10.1136/jmg.2004.024646 · Cited by 778 · see citing works
Tang, S. J., Reis, G., Kang, H., Gingras, A.-C., Sonenberg, N., & Schuman, E. M. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.012605299 · Cited by 734 · see citing works
Metabotropic glutamate receptors: Synaptic transmission, modulation, and plasticity
Nakanishi, S. (1994) · Neuron · doi:10.1016/0896-6273(94)90043-4 · Cited by 716 · see citing works
Nojima, H., Tokunaga, C., Eguchi, S., Oshiro, N., Sujuti, H., Yoshino, K., Hara, K., Tanaka, N., Avruch, J., & Yonezawa, K. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c200665200 · Cited by 678 · see citing works
Weiler, 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 · cited 2× · see citing works
“, 2006) and drives mTORdependent protein synthesis in dendrites (Weiler et al., 1997).”
BackgroundTwo distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells.
Oliet, S., Malenka, R., & Nicoll, R. (1997) · Neuron · doi:10.1016/s0896-6273(00)80336-0 · Cited by 600 · see citing works
Hou, L., & Klann, E. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.0995-04.2004 · Cited by 527 · see citing works
Self-citationSmalley, S. L., Tanguay, P. E., Smith, M., & Gutierrez, G. (1992) · Journal of Autism and Developmental Disorders · doi:10.1007/bf01048239 · Cited by 518 · see citing works
RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice
Miyashiro, K. Y., Beckel-Mitchener, A., Purk, T. P., Becker, K. G., Barret, T., Liu, L., Carbonetto, S., Weiler, I. J., Greenough, W. T., & Eberwine, J. (2003) · Neuron · doi:10.1016/s0896-6273(03)00034-5 · Cited by 495 · see citing works
mTOR Complex1–S6K1 signaling: at the crossroads of obesity, diabetes and cancer
Dann, S. G., Selvaraj, A., & Thomas, G. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.04.002 · Cited by 481 · 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
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
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
Self-citationProtean PTEN: Form and Function
Waite, K. A., & Eng, C. (2002) · The American Journal of Human Genetics · doi:10.1086/340026 · Cited by 457 · see citing works
Biochemical mechanisms for translational regulation in synaptic plasticity
Klann, E., & Dever, T. E. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1557 · Cited by 422 · see citing works
Self-citationThe Pathophysiology of Fragile X Syndrome
Penagarikano, O., Mulle, J. G., & Warren, S. T. (2007) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.8.080706.092249 · Cited by 420 · see citing works
Translational Suppression by Trinucleotide Repeat Expansion at <i>FMR1</i>
Feng, Y., Zhang, F., Lokey, L. K., Chastain, J. L., Lakkis, L., Eberhart, D., & Warren, S. T. (1995) · Science · doi:10.1126/science.7732383 · Cited by 358 · see citing works
Palmer, M. J., Irving, A. J., Seabrook, G. R., Jane, D. E., & Collingridge, G. L. (1997) · Neuropharmacology · doi:10.1016/s0028-3908(97)00181-0 · Cited by 338 · 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
PI3 kinase enhancer–Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis
Rong, R., Ahn, J.-Y., Huang, H., Nagata, E., Kalman, D., Kapp, J. A., Tu, J., Worley, P. F., Snyder, S. H., & Ye, K. (2003) · Nature Neuroscience · doi:10.1038/nn1134 · Cited by 281 · see citing works
Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1
Jacquemont, S., Hagerman, R. J., Hagerman, P. J., & Leehey, M. A. (2006) · The Lancet Neurology · doi:10.1016/s1474-4422(06)70676-7 · Cited by 277 · see citing works
Vries, B. B. A. D., Halley, D. J. J., Oostra, B. A., & Niermeijer, M. F. (1998) · Journal of Medical Genetics · doi:10.1136/jmg.35.7.579 · Cited by 260 · see citing works
The fragile X premutation: into the phenotypic fold
Hagerman, R. J., & Hagerman, P. J. (2002) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(02)00299-x · Cited by 259 · see citing works
Banko, J. L., Hou, L., Poulin, F., Sonenberg, N., & Klann, E. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.5196-05.2006 · Cited by 245 · see citing works
Self-citationRonesi, J. A., & Huber, K. M. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5019-07.2008 · Cited by 244 · see citing works
Metabotropic glutamate receptors trigger postsynaptic protein synthesis.
Weiler, I. J., & Greenough, W. T. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.15.7168 · Cited by 244 · see citing works
PTEN signaling in brain: neuropathology and tumorigenesis
Endersby, R., & Baker, S. J. (2008) · Oncogene · doi:10.1038/onc.2008.239 · Cited by 222 · see citing works
Understanding PTEN regulation: PIP2, polarity and protein stability
Leslie, N. R., Batty, I. H., Maccario, H., Davidson, L., & Downes, C. P. (2008) · Oncogene · doi:10.1038/onc.2008.243 · Cited by 221 · see citing works
PTEN mutation in a family with Cowden syndrome and autism
Goffin, A., Hoefsloot, L. H., Bosgoed, E., Swillen, A., & Fryns, J. (2001) · American Journal of Medical Genetics · doi:10.1002/ajmg.1477 · Cited by 215 · see citing works
Wiznitzer, M. (2004) · Journal of Child Neurology · doi:10.1177/08830738040190090701 · Cited by 214 · see citing works
Price, T. J., Rashid, M. H., Millecamps, M., Sanoja, R., Entrena, J. M., & Cerveró, F. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4383-07.2007 · Cited by 210 · see citing works
New insights into fragile X syndrome: from molecules to neurobehaviors
Jin, P., & Warren, S. T. (2003) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(03)00033-1 · Cited by 203 · see citing works
Protein translation in synaptic plasticity: mGluR-LTD, Fragile X
Waung, M. W., & Huber, K. M. (2009) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2009.03.011 · Cited by 174 · see citing works
Ye, K., Hurt, K. J., Wu, F. Y., Fang, M., Luo, H. R., Hong, J. J., Blackshaw, S., Ferris, C. D., & Snyder, S. H. (2000) · Cell · doi:10.1016/s0092-8674(00)00195-1 · Cited by 148 · 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
Raptor and mTOR: Subunits of a Nutrient-Sensitive Complex
Kim, D., & Sabatini, D. M. (2004) · Current topics in microbiology and immunology · doi:10.1007/978-3-642-18930-2_15 · Cited by 136 · see citing works
Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X
Loesch, D. Z., Bui, M., Dissanayake, C., Clifford, S. M., Gould, E. L., Bulhak‐Paterson, D., Tassone, F., Taylor, A. K., Hessl, D. R., Hagerman, R. J., et al. (2006) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2006.09.007 · Cited by 132 · see citing works
Altered Hippocampal Synaptic Plasticity in the <i>Fmr1</i> Gene Family Knockout Mouse Models
Zhang, J., Hou, L., Klann, E., & Nelson, D. L. (2009) · Journal of Neurophysiology · doi:10.1152/jn.90558.2008 · Cited by 126 · see citing works
Self-citationAngenstein, F., Greenough, W. T., & Weiler, I. J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.15078 · Cited by 78 · see citing works
Protein synthesis in the dendrite
Tang, S. J., & Schuman, E. M. (2002) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2001.0887 · Cited by 69 · see citing works
Sumita, D. R., Vainzof, M., Campiotto, S., Cerqueira, A., C�novas, M., Otto, P. A., Passos-Bueno, M. R., & Zatz, M. (1998) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19981204)80:4 · Cited by 43 · see citing works
Kinase signaling pathways as potential targets in the treatment of Parkinson’s disease
Greggio, E., & Singleton, A. (2007) · Expert Review of Proteomics · doi:10.1586/14789450.4.6.783 · Cited by 24 · see citing works
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- Ye K Hurt KJ Wu FY Fang M Luo HR Hong JJ Blackshaw S Ferris CD Snyder SH 2000 Pike. A nuclear gtpase that enhances PI3kinase activity and is regulated by protein 4.1N Cell 103 919 930 11136977
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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 · see citing works
mTOR signaling: At the crossroads of plasticity, memory and disease
Hoeffer, C. A., & Klann, E. (2010) · Trends in Neurosciences · doi:10.1016/j.tins.2009.11.003 · Cited by 1,128 · see citing works
Self-citationConvergence of genes and cellular pathways dysregulated in autism spectrum disorders
Pinto, D., Delaby, E., Merico, D., Barbosa, M., Merikangas, A., Klei, L., Thiruvahindrapuram, B., Xu, X., Ziman, R., Wang, Z., et al. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.03.018 · Cited by 969 · see citing works
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 · see citing works
FMRP targets distinct mRNA sequence elements to regulate protein expression
Ascano, M., Mukherjee, N., Bandaru, P., Miller, J. B., Nusbaum, J. D., Corcoran, D. L., Langlois, C., Munschauer, M., Dewell, S., Hafner, M., et al. (2012) · Nature · doi:10.1038/nature11737 · Cited by 701 · see citing works
Mutations causing syndromic autism define an axis of synaptic pathophysiology
Auerbach, B. D., Osterweil, E. K., & Bear, M. F. (2011) · Nature · doi:10.1038/nature10658 · Cited by 592 · see citing works
Gao, R., & Penzes, P. (2015) · Current Molecular Medicine · doi:10.2174/1566524015666150303003028 · Cited by 516 · see citing works
Structural plasticity upon learning: regulation and functions
Caroni, P., Donato, F., & Muller, D. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3258 · Cited by 491 · see citing works
Chronic Pharmacological mGlu5 Inhibition Corrects Fragile X in Adult Mice
Michalon, A., Sidorov, M., Ballard, T. M., Ozmen, L., Spooren, W., Wettstein, J. G., Jaeschke, G., Bear, M. F., & Lindemann, L. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.009 · Cited by 489 · see citing works
The translation of translational control by FMRP: therapeutic targets for FXS
Darnell, J. C., & Klann, E. (2013) · Nature Neuroscience · doi:10.1038/nn.3379 · Cited by 491 · see citing works
Self-citationOsterweil, 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
Translational control in synaptic plasticity and cognitive dysfunction
Buffington, S. A., Huang, W., & Costa-Mattioli, M. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014100 · Cited by 348 · 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
Bhattacharya, A., Kaphzan, H., Alvarez-Dieppa, A. C., Murphy, J. P., Pierre, P., & Klann, E. (2012) · Neuron · doi:10.1016/j.neuron.2012.07.022 · Cited by 316 · see citing works
Self-citationmTORC2 controls actin polymerization required for consolidation of long-term memory
Huang, W., Zhu, P. J., Zhang, S., Zhou, H., Stoica, L., Galiano, M., Krnjević, K., Roman, G., & Costa-Mattioli, M. (2013) · Nature Neuroscience · doi:10.1038/nn.3351 · Cited by 307 · see citing works
Dysregulation and restoration of translational homeostasis in fragile X syndrome
Richter, J. D., Bassell, G. J., & Klann, E. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn4001 · Cited by 275 · see citing works
Self-citationDifferential role of anandamide and 2-arachidonoylglycerol in memory and anxiety-like responses
Busquets-Garcia, A., Puighermanal, E., Pastor, A., de la Torre, R., Maldonado, R., & Ozaita, A. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.04.022 · Cited by 273 · 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
Fragile X and autism: intertwined at the molecular level leading to targeted treatments
Hagerman, R., Hoem, G., & Hagerman, P. (2010) · Molecular Autism · doi:10.1186/2040-2392-1-12 · Cited by 247 · see citing works
Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome
Ronesi, J. A., Collins, K. A., Hays, S. A., Tsai, N.-P., Guo, W., Birnbaum, S. G., Hu, J.-H., Worley, P. F., Gibson, J. R., & Huber, K. M. (2012) · Nature Neuroscience · doi:10.1038/nn.3033 · Cited by 251 · 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
Targeting the endocannabinoid system in the treatment of fragile X syndrome
Busquets-Garcia, A., Gomis-González, M., Guegan, T., Agustín-Pavón, C., Pastor, A., Mato, S., Pérez-Samartín, A., Matute, C., de la Torre, R., Dierssen, M., et al. (2013) · Nature Medicine · doi:10.1038/nm.3127 · Cited by 241 · 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
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
Loss of Tsc1 In Vivo Impairs Hippocampal mGluR-LTD and Increases Excitatory Synaptic Function
Bateup, H. S., Takasaki, K. T., Saulnier, J. L., Denefrio, C. L., & Sabatini, B. L. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.1617-11.2011 · Cited by 204 · see citing works
Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome
Hoeffer, C. A., Sanchez, E., Hagerman, R. J., Mu, Y., Nguyen, D. V., Wong, H., Whelan, A. M., Zukin, R. S., Klann, E., & Tassone, F. (2012) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2012.00768.x · Cited by 198 · see citing works
Self-citationGkogkas, C. G., Khoutorsky, A., Cao, R., Jafarnejad, S. M., Prager-Khoutorsky, M., Giannakas, N., Kaminari, A., Fragkouli, A., Nader, K., Price, T. J., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.064 · Cited by 201 · see citing works
Lombardo, M. V., Moon, H. M., Su, J., Palmer, T. D., Courchesne, E., & Pramparo, T. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.15 · Cited by 201 · see citing works
Dysregulation of Mammalian Target of Rapamycin Signaling in Mouse Models of Autism
Huber, K. M., Klann, E., Costa-Mattioli, M., & Zukin, R. S. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2656-15.2015 · Cited by 167 · see citing works
Self-citationThe 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
Sidhu, H., Dansie, L. E., Hickmott, P. W., Ethell, D. W., & Ethell, I. M. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.1162-14.2014 · Cited by 155 · see citing works
Yang, F., Chu, X., Yin, M., Liu, X., Yuan, H., Niu, Y., & Fu, L. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.02.005 · Cited by 136 · see citing works
Huang, W.-C., Chen, Y., & Page, D. T. (2016) · Nature Communications · doi:10.1038/ncomms13421 · Cited by 130 · see citing works
Santini, E., & Klann, E. (2014) · Science Signaling · doi:10.1126/scisignal.2005832 · Cited by 118 · see citing works
Self-citationVeenstra-VanderWeele, J., & Blakely, R. D. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.185 · Cited by 128 · see citing works
Gross, C., Chang, C.-W., Kelly, S. M., Bhattacharya, A., McBride, S. M. J., Danielson, S. W., Jiang, M. Q., Chan, C. B., Ye, K., Gibson, J. R., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.03.060 · Cited by 117 · 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
Ehninger, D., Sano, Y., de Vries, P. J., Dies, K., Franz, D., Geschwind, D. H., Kaur, M., Lee, Y.-S., Li, W., Lowe, J. K., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2010.115 · Cited by 120 · see citing works
The Fragile X mental retardation protein regulates matrix metalloproteinase 9 mRNA at synapses.
Janusz, A., Miłek, J., Perycz, M., Pacini, L., Bagni, C., Kaczmarek, L., & Dziembowska, M. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.2207-13.2013 · Cited by 112 · see citing works
TSC1/TSC2 signaling in the CNS
Han, J. M., & Sahin, M. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.02.001 · Cited by 105 · 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
Higashimori, H., Schin, C. S., Chiang, M. S. R., Morel, L., Shoneye, T. A., Nelson, D. L., & Yang, Y. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1069-16.2016 · Cited by 105 · see citing works
Genetic basis of autism: is there a way forward?
Eapen, V. (2011) · Current Opinion in Psychiatry · doi:10.1097/yco.0b013e328345927e · Cited by 102 · 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
Berry-Kravis, E., Horrigan, J. P., Tartaglia, N., Hagerman, R., Kolevzon, A., Erickson, C. A., Hatti, S., Snape, M., Yaroshinsky, A., Stoms, G., et al. (2020) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2020.04.019 · Cited by 102 · 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
Monyak, R. E., Emerson, D., Schoenfeld, B. P., Zheng, X., Chambers, D. B., Rosenfelt, C., Langer, S., Hinchey, P., Choi, C. H., McDonald, T. V., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.51 · Cited by 100 · see citing works
Self-citationFMR1 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 · see citing works
Sawicka, 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 · see citing works
Self-citationChévere-Torres, I., Kaphzan, H., Bhattacharya, A., Kang, A., Maki, J. M., Gambello, M. J., Arbiser, J. L., Santini, E., & Klann, E. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.12.028 · Cited by 83 · see citing works
Self-citationTsai, P., & Sahin, M. (2011) · Current Opinion in Neurology · doi:10.1097/wco.0b013e32834451c4 · Cited by 84 · see citing works
NNZ-2566, a novel analog of (1–3) IGF-1, as a potential therapeutic agent for fragile X syndrome
Deacon, R. M. J., Glass, L., Snape, M., Hurley, M. J., Altimiras, F. J., Biekofsky, R. R., & Cogram, P. (2015) · NeuroMolecular Medicine · doi:10.1007/s12017-015-8341-2 · Cited by 78 · 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
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 · see citing works
Sarnat, H. B., & Flores-Sarnat, L. (2015) · Brain and Development · doi:10.1016/j.braindev.2014.08.010 · Cited by 73 · see citing works
The Gut-Immune-Brain Axis in Autism Spectrum Disorders; A Focus on Amino Acids
van Sadelhoff, J. H. J., Perez Pardo, P., Wu, J., Garssen, J., van Bergenhenegouwen, J., Hogenkamp, A., Hartog, A., & Kraneveld, A. D. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00247 · Cited by 71 · see citing works
Radwan, B., Dvorak, D., & Fenton, A. A. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.01.003 · Cited by 63 · see citing works
Qin, M., Huang, T., Kader, M., Krych, L., Xia, Z., Burlin, T., Zeidler, Z., Zhao, T., & Smith, C. B. (2015) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyv034 · Cited by 62 · see citing works
Abekhoukh, S., Sahin, H. B., Grossi, M., Zongaro, S., Maurin, T., Madrigal, I., Kazue-Sugioka, D., Raas-Rothschild, A., Doulazmi, M., Carrera, P., et al. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.025809 · Cited by 59 · see citing works
“This alteration is not due to an altered expression of mTor (Sharma et al., 2010), but rather to the overactivation of PI3K, because of the overexpression of the catalytic PI3K subunit p110 β (Gross et al., 2010; Gross and Bassell, 2012).”
InfluentialWang, H., Kim, S. S., & Zhuo, M. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.116293 · Cited by 52 · see citing works
Intergenerational Metabolic Syndrome and Neuronal Network Hyperexcitability in Autism
Rivell, A., & Mattson, M. P. (2019) · Trends in Neurosciences · doi:10.1016/j.tins.2019.08.006 · Cited by 50 · see citing works
Rapamycin reveals an mTOR-independent repression of Kv1.1 expression during epileptogenesis
Sosanya, N. M., Brager, D. H., Wolfe, S., Niere, F., & Raab-Graham, K. F. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.09.011 · Cited by 49 · see citing works
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 · see citing works
Self-citationNiere, F., Namjoshi, S., Song, E., Dilly, G. A., Schoenhard, G., Zemelman, B. V., Mechref, Y., & Raab-Graham, K. F. (2016) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m115.055079 · Cited by 38 · 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
Boda, B., Mendez, P., Boury‐Jamot, B., Magara, F., & Muller, D. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12488 · Cited by 30 · see citing works
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 · see citing works
Reyes, S. T., Deacon, R. M. J., Guo, S. G., Altimiras, F. J., Castillo, J. B., van der Wildt, B., Morales, A. P., Park, J. H., Klamer, D., Rosenberg, J., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-94079-7 · Cited by 22 · see citing works
Kong, S. W., Sahin, M., Collins, C. D., Wertz, M. H., Campbell, M. G., Leech, J. D., Krueger, D., Bear, M. F., Kunkel, L. M., & Kohane, I. S. (2014) · Molecular Autism · doi:10.1186/2040-2392-5-16 · Cited by 19 · see citing works
- Authors
- Sharma, A., Hoeffer, C. A., Takayasu, Y., Miyawaki, T., McBride, S. M., Klann, E., & Zukin, R. S.
- Affiliations
- Albert Einstein College of Medicine (US)
- New York University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-01-13
- Volume
- 30
- Issue
- 2
- Pages
- 694-702
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3665010
- OpenAlex
- W2089756166
- Cited by
- 557
- References
- 55
- Citations by year
- 2026: 15 · 2025: 13 · 2024: 21 · 2023: 19 · 2022: 23 · 2021: 38 · 2020: 41 · 2019: 30 · 2018: 26 · 2017: 31 · 2016: 47 · 2015: 43 · 2014: 50 · 2013: 46 · 2012: 43
- FWCI
- 28.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- Autism Speaks (AS2087)
- National Institutes of Health (N S04738 4)
- National Institute of Neurological Disorders and Stroke (NS-047384, NS340007, NS-20752, R01NS020752, R01NS047384)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- fragile X syndrome, mTOR signaling, FMRP, Fmr1 knockout mice, metabotropic glutamate receptors, long-term depression, CA1 synapses, synaptic plasticity, cap-dependent translation, eIF4F, S6 kinase, pike, hippocampus, autism spectrum disorder, intellectual disability
- MeSH terms
- Animals, Carrier Proteins, Cognition Disorders, Disease Models, Animal, Fragile X Syndrome, Gene Expression Regulation, Methoxyhydroxyphenylglycol, Phosphoproteins, Phosphorylation, Serine, Signal Transduction, Receptors, Metabotropic Glutamate, Mice, Knockout, Cell Cycle Proteins, Excitatory Postsynaptic Potentials, Phosphatidylinositol 3-Kinases, Sirolimus, Long-Term Synaptic Depression, Eukaryotic Initiation Factor-4A, Eukaryotic Initiation Factors, Immunoprecipitation, Adaptor Proteins, Signal Transducing, Oncogene Protein v-akt, Mice, Fragile X Messenger Ribonucleoprotein 1, CA1 Region, Hippocampal, In Vitro Techniques
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