Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation

Weiler, Ivan Jeanne; Irwin, Scott A.; Klintsova, Anna Y.; Spencer, Corinne M.; Brazelton, Anthony D.; Miyashiro, Kevin; Comery, Thomas A.; Patel, Bindu; Eberwine, James; Greenough, William T.

doi:10.1073/pnas.94.10.5395

Cited by 644Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchRNA and protein synthesis mechanisms

Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation

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Weiler, Ivan Jeanne, Irwin, Scott A., Klintsova, Anna Y., Spencer, Corinne M., Brazelton, Anthony D., Miyashiro, Kevin, Comery, Thomas A., Patel, Bindu +2 more·1997·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.94.10.5395PMC PMC24689

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Abstract

Local translation of proteins in distal dendrites is thought to support synaptic structural plasticity. We have previously shown that metabotropic glutamate receptor (mGluR1) stimulation initiates a phosphorylation cascade, triggering rapid association of some mRNAs with translation machinery near synapses, and leading to protein synthesis. To determine the identity of these mRNAs, a cDNA library produced from distal nerve processes was used to screen synaptic polyribosome-associated mRNA. We identified mRNA for the fragile X mental retardation protein (FMRP) in these processes by use of synaptic subcellular fractions, termed synaptoneurosomes. We found that this mRNA associates with translational complexes in synaptoneurosomes within 1-2 min after mGluR1 stimulation of this preparation, and we observed increased expression of FMRP after mGluR1 stimulation. In addition, we found that FMRP is associated with polyribosomal complexes in these fractions. In vivo, we observed FMRP immunoreactivity in spines, dendrites, and somata of the developing rat brain, but not in nuclei or axons. We suggest that rapid production of FMRP near synapses in response to activation may be important for normal maturation of synaptic connections.

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DHPG stimulates dendritic translation of FMRP.
“In fact, in both assays there was more FMRP immunoprecipitated from the DHPG-treated WT SNs, which is in agreement with previous reports that DHPG stimulates the dendritic translation of FMRP [22,39].”
From FMRP Mediates mGluR5-Dependent Translation of Amyloid Precursor Protein (2007) · cites this paper as [39]

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“FMRP is localized to synapses, where evidence suggests that it regulates mRNA translation following the activation of type I mGluRs, although this has not been formally prove”
Background
Dysregulation of mTOR signaling in fragile X syndrome
Sharma, A., Hoeffer, C. A., Takayasu, Y., Miyawaki, T., McBride, S. M., Klann, E., & Zukin, R. S. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.3696-09.2010 · Cited by 557 · see citing works
“, 2006) and drives mTORdependent protein synthesis in dendrites (Weiler et al., 1997).”
Background
Abnormal Development of Dendritic Spines inFMR1Knock-Out Mice
Nimchinsky, E. A., Oberlander, A. M., & Svoboda, K. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-14-05139.2001 · Cited by 560 · see citing works
“is significant that FMRP expression is increased by afferent stimulation (Todd and Mack, 2000) and that there is evidence for local translation of FMRP in response to metabotropic glutamate receptor stimulation (Weiler and Greenough, 1993; Weiler et al., 1997).”
Background
Molecular Mechanisms of Fragile X Syndrome: A Twenty-Year Perspective
Santoro, M. R., Bray, S. M., & Warren, S. T. (2012) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-011811-132457 · Cited by 528 · 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 direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome
Dictenberg, J. B., Swanger, S. A., Antar, L. N., Singer, R. H., & Bassell, G. J. (2008) · Developmental Cell · doi:10.1016/j.devcel.2008.04.003 · Cited by 511 · 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
Normally occurring environmental and behavioral influences on gene activity: From central dogma to probabilistic epigenesis
Gottlieb, G. (1998) · Psychological Review · doi:10.1037/0033-295x.105.4.792-802 · Cited by 489 · see citing works
Dynamic Translational and Proteasomal Regulation of Fragile X Mental Retardation Protein Controls mGluR-Dependent Long-Term Depression
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
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
“FMR1mRNA is present in synaptoneurosome preparations thought to be highly enriched for synapses (Weiler et al. 1997).”
Background
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
“FMR1 is one such cargo mRNA, and is translated at synapses in response to the activation of group I metabotropic glutamate receptors (mGluR1s”
Background
Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression
Hou, L., & Klann, E. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.0995-04.2004 · Cited by 527 · see citing works
“, 1997), and stimulation of mGluRs has been shown to result in a rapid translation of FMRP in synaptoneurosomes (Weiler et al., 1997).”
Mechanisms governing activity-dependent synaptic pruning in the developing mammalian CNS
Faust, T. E., Gunner, G., & Schafer, D. P. (2021) · Nature reviews. Neuroscience · doi:10.1038/s41583-021-00507-y · Cited by 440 · see citing works
Autism as a disorder of neural information processing: Directions for research and targets for therapy
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
“involves FMRP occurs at synapses in response to Group I metabotropic receptor activation [257].”
Background
Dysregulated Metabotropic Glutamate Receptor-Dependent Translation of AMPA Receptor and Postsynaptic Density-95 mRNAs at Synapses in a Mouse Model of Fragile X Syndrome
Muddashetty, R. S., Kelić, S., Gross, C., Xu, M., & Bassell, G. J. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.0937-07.2007 · Cited by 421 · 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
“In addition, membrane depolarization, BDNF and glutamate receptor agonists induce the synthesis of new proteins in isolated dendrites and synaptoneurosome”
Background
The 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
Deletion of FMR1 in Purkinje Cells Enhances Parallel Fiber LTD, Enlarges Spines, and Attenuates Cerebellar Eyelid Conditioning in Fragile X Syndrome
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
“Indeed, FMRP and Fmr1 mRNA are present in spines and/or dendrites, and FMRP is translated in response to activation of the type 1 metabotropic glutamate receptors (mGluR-1) in synaptoneurosomes (Weiler et al., 1997).”
Background
The fragile X mental retardation protein binds specifically to its mRNA via a purine quartet motif
Schaeffer, C., Bardoni, B., Mandel, J., Ehresmann, B., Ehresmann, C., & Moine, H. (2001) · The EMBO Journal · doi:10.1093/emboj/20.17.4803 · Cited by 471 · see citing works
Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites
Takei, N., Inamura, N., Kawamura, M., Namba, H., Hara, K., Yonezawa, K., & Nawa, H. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.1427-04.2004 · Cited by 442 · see citing works
“, 1997), and fragileX mental retardation protein (FMRP) (Weiler et al., 1997) were shown to localize at dendrites (Kiebler and DesGroseillers, 2000; Job and Eberwine, 2001).”
BackgroundInfluential
Metabotropic Glutamate Receptor Activation Regulates Fragile X Mental Retardation Protein and Fmr1 mRNA Localization Differentially in Dendrites and at Synapses
Antar, L. N., Afroz, R., Dictenberg, J. B., Carroll, R. C., & Bassell, G. J. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.0099-04.2004 · Cited by 389 · see citing works
“…is linked to long-term synaptic plasticity (Bonhoeffer and Yuste, 2002), and increased FMRP expression in response to activity has been observed in synaptosomes after exposure to glutamate receptor (GluR) agonists (Weiler et al., 1997) or whisker-pad stimulation in vivo (Todd and Mack, 2000).”
Hypersensitivity to mGluR5 and ERK1/2 Leads to Excessive Protein Synthesis in the Hippocampus of a Mouse Model of Fragile X Syndrome
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
“Group 1 (Gp1) metabotropic glutamate receptors (mGluR1 and mGluR5) stimulate mRNA translation at synapses (Weiler and Greenough, 1993; Weiler et al., 1997) and many lasting physiological consequences of Gp1 mGluR activation require rapid synaptic protein synthesis (Merlin et al.”
Compartmentalized Synthesis and Degradation of Proteins in Neurons
Steward, O., & Schuman, E. M. (2003) · Neuron · doi:10.1016/s0896-6273(03)00635-4 · Cited by 380 · see citing works
“, 2000), and the mRNA for -actin (Tiruchinapalli et 2000), Fragile X mental retardation protein (FMRP; Weiler et al., 1997), and Arc (Zalfa et al.”
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
“The early finding that FMRP can be synthesized in response to mGluR activation (Weiler et al. 1997) led to the study of LTD in the Fmr1-KO mouse (Huber et al. 2002).”
Background
Trapping of messenger RNA by Fragile X Mental Retardation protein into cytoplasmic granules induces translation repression
Mazrouï, R. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.24.3007 · Cited by 369 · see citing works
“(12) have shown that Fmr1 mRNA is present in isolated synaptosomes purified from rat brain and that this mRNA is rapidly taken up into polyribosomes in response to stimulation by agonists for phosphoinositide-coupled metabotropic glutamate receptors.”
Background
Understanding the molecular basis of fragile X syndrome
Jin, P. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.6.901 · Cited by 368 · see citing works
“The regulation of synaptic-activitydependent protein synthesis by FMRP is further supported by the observation that the translation of FMRP was increased in rat synaptoneurosomes after stimulation by a specific mGluR agonist (80).”
Background
Genetics of Early Onset Cognitive Impairment
Ropers, H. (2010) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-082509-141640 · Cited by 365 · see citing works
A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stability
Zalfa, F., Eleuteri, B., Dickson, K. S., Mercaldo, V., Rubeis, S. D., di Penta, A., Tabolacci, E., Chiurazzi, P., Neri, G., Grant, S. G. N., et al. (2007) · Nature Neuroscience · doi:10.1038/nn1893 · Cited by 364 · see citing works
Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome
Berry-Kravis, E. M., Lindemann, L., Jønch, A. E., Apostol, G., Bear, M. F., Carpenter, R. L., Crawley, J. N., Curie, A., Des Portes, V., Hossain, F., et al. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.221 · Cited by 336 · see citing works
NMDA receptor-mediated control of protein synthesis at developing synapses
Scheetz, A. J., Nairn, A. C., & Constantine‐Paton, M. (2000) · Nature Neuroscience · doi:10.1038/72915 · Cited by 362 · see citing works
“For example, synthesis of the fragile X protein is increased by activation of metabotropic glutamate receptors in synaptoneurosome”
Background
Sleep and Synaptic Homeostasis: Structural Evidence in Drosophila
Bushey, D., Tononi, G., & Cirelli, C. (2011) · Science · doi:10.1126/science.1202839 · Cited by 357 · see citing works
Chemical Stimulation of Synaptosomes Modulates α-Ca2+/Calmodulin-Dependent Protein Kinase II mRNA Association to Polysomes
Bagni, C., Mannucci, L., Dotti, C. G., & Amaldi, F. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-10-j0004.2000 · Cited by 357 · see citing works
“A similar approach has been previously used to analyze translation of fragile X mental retardation protein mRNA (Weiler and Greenough, 1993; Weiler et al., 1997).”
Method
Rho GTPases, dendritic structure, and mental retardation
Newey, S. E., Velamoor, V., Govek, E., & Van Aelst, L. (2005) · Journal of Neurobiology · doi:10.1002/neu.20153 · Cited by 351 · see citing works
“Although both FMRP and Rac1 have been observed in dendritic spines (Weiler et al., 1997; Nakayama et al., 2000), FMRP has only recently been linked directly to Rac signaling.”
Background
Molecular mechanisms of dendritic spine development and remodeling
Ethell, I. M., & Pasquale, E. B. (2005) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2005.02.003 · Cited by 349 · see citing works
FMRP expression as a potential prognostic indicator in fragile X syndrome
Tassone, F., Hagerman, R. J., Ikl�, D. N., Dyer, P. N., Lampe, M., Willemsen, R., Oostra, B. A., & Taylor, A. K. (1999) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19990528)84:3 · Cited by 341 · see citing works
Fragile X syndrome and autism at the intersection of genetic and neural networks
Belmonte, M. K., & Bourgeron, T. (2006) · Nature Neuroscience · doi:10.1038/nn1765 · Cited by 345 · see citing works
“1): (1) an anomaly in synapse formation or maintenance, (2) an imbalance between excitation and inhibition45, (3) abnormal cell number and (4) abnormal neuromodulatory function affecting network properties.”
Background
Overview of glutamatergic neurotransmission in the nervous system
Niciu, M. J., Kelmendi, B., & Sanacora, G. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.08.008 · Cited by 335 · see citing works
“Beyond its enhancing effects on ionotropic glutamate receptor activation, mGluR5 has been demonstrated to play a role in regulating local mRNA translation in dendritic spines (Weiler & Greenough, 1993; Weiler et al., 1997).”
CYFIP/Sra-1 controls neuronal connectivity in Drosophila and links the Rac1 GTPase pathway to the fragile X protein.
Schenck, 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
“FMRP is present at synapses and can act Institut de Génétique et de Biologie as a translational regulator (Weiler et al., 1997; LaggerMoléculaire et Cellulaire bauer et al., 2001; Li et al., 2001; Brown et al., 2001; CNRS/INSERM/ULP, Boite Postale 10142 Miyashiro et al., 2003; Zalfa et al., 2003).”
Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice
de Vrij, F. M. S., Levenga, J., van der Linde, H. C., Koekkoek, S. K., De Zeeuw, C. I., Nelson, D. L., Oostra, B. A., & Willemsen, R. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.04.002 · Cited by 313 · see citing works
“Therefore, FMRP is thought to be involved in the transport and/or the regulation of local mRNA translation at synaptic sites (Bagni and Greenough, 2005; Miyashiro et al., 2003; Weiler et al., 1997, 2004).”
Background
A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P
Schenck, A., Bardoni, B., Moro, A., Bagni, C., & Mandel, J.-L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.151231598 · Cited by 356 · see citing works
Phenotypic variation and FMRP levels in fragile X
Loesch, D. Z., Huggins, R., & Hagerman, R. J. (2004) · Mental Retardation and Developmental Disabilities Research Reviews · doi:10.1002/mrdd.20006 · Cited by 299 · see citing works
“…in the cerebral cortex, cerebellum, and hippocampus [Willemsen et al., 1995; Irwin et al., 2002; Mineur et al., 2002] and in modifying synaptic structure in response to environmental stimulation [Weiler et al., 1997; Weiler and Greenough 1999; Beckel-Mitchener and Greenough, this volume).”
Background
Brain Waves and Brain Wiring: The Role of Endogenous and Sensory-Driven Neural Activity in Development
Penn, A. A., & Shatz, C. J. (1999) · Pediatric Research · doi:10.1203/00006450-199904010-00001 · Cited by 294 · 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
“DHPG stimulates the dendritic translation of FMRP [22,39].”
Background
Metabotropic Receptor-Dependent Long-Term Depression Persists in the Absence of Protein Synthesis in the Mouse Model of Fragile X Syndrome
Nosyreva, E. D., & Huber, K. M. (2006) · Journal of Neurophysiology · doi:10.1152/jn.01316.2005 · Cited by 292 · see citing works
“Clues to the synaptic role of FMRP emerged when FMRP was found to be synthesized in synaptoneurosomes in response to group 1 metabotropic glutamate receptor (mGluR) activation (Weiler et al. 1997).”
Background
(Over)correction of FMR1 deficiency with YAC transgenics: behavioral and physical features
Peier, A. M. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.8.1145 · Cited by 285 · see citing works
“observed after metabotrobic glutamate stimulation (67), is suggestive of a role for FMRP in synaptic function.”
Background
Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice
Hayashi, M. L., Rao, B. S. S., Seo, J.-S., Choi, H.-S., Dolan, B. M., Choi, S.-Y., Chattarji, S., & Tonegawa, S. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705003104 · Cited by 281 · see citing works
Drosophila Lacking dfmr1 Activity Show Defects in Circadian Output and Fail to Maintain Courtship Interest
Dockendorff, T. C., Su, H. S., McBride, S. M. J., Yang, Z., Choi, C. H., Siwicki, K. K., Sehgal, A., & Jongens, T. A. (2002) · Neuron · doi:10.1016/s0896-6273(02)00724-9 · Cited by 284 · see citing works
Neural plasticity, joint attention, and a transactional social-orienting model of autism
(2000) · International Review of Research in Mental Retardation · doi:10.1016/s0074-7750(00)80009-9 · Cited by 284 · see citing works
“FMRP expression at synapsis is thought to be involved in activity dependent synapse maturation and therefore be integral to neural plasticity (Black et al. 1998; Weiler et al. 1997).”
Background
Characterization of dFMR1, a Drosophila melanogaster Homolog of the Fragile X Mental Retardation Protein
Wan, L., Dockendorff, T. C., Jongens, T. A., & Dreyfuss, G. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.22.8536-8547.2000 · Cited by 280 · see citing works
“Loss of function of FMR1 in mice leads to abnormalities in dendritic spine processing and maturation, and FMR1 mRNA is rapidly translated in response to neurotransmitter at synapses (15, 67).”
Background
Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome
Dölen, G., & Bear, M. F. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.150722 · Cited by 278 · see citing works
“Signalling by group 1 (Gp1) mGluRs occurs postsynaptically via Gq second messenger cascades, and it is now clear that one consequence at many synapses is stimulation of local protein synthesis (Weiler & Greenough, 1993; Weiler et al. 1997).”
Background
miR-124a is required for hippocampal axogenesis and retinal cone survival through Lhx2 suppression
Sanuki, R., Onishi, A., Koike, C., Muramatsu, R., Watanabe, S., Muranishi, Y., Irie, S., Uneo, S., Koyasu, T., Matsui, R., et al. (2011) · Nature Neuroscience · doi:10.1038/nn.2897 · Cited by 278 · see citing works
“A recent study of FMRP, a protein that is involved in a fragile X syndrome and a RISC component interacting with Argonaute, suggested that miR-124a interacts with the FMRP protein, which is present at synapse”
Background
Disruption of RNA Metabolism in Neurological Diseases and Emerging Therapeutic Interventions
Nussbacher, J. K., Tabet, R., Yeo, G. W.-M., & Lagier‐Tourenne, C. (2019) · Neuron · doi:10.1016/j.neuron.2019.03.014 · Cited by 274 · see citing works
“, 2008) and localizes to the postsynaptic spaces of dendritic spines where it may function as a translational repressor influencing local protein synthesis (Feng et al., 1997; Sch€ utt et al., 2009; Weiler et al., 1997; Zalfa et al., 2003).”
Background
Reduced Cortical Synaptic Plasticity and GluR1 Expression Associated with Fragile X Mental Retardation Protein Deficiency
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 271 · 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
Postadolescent Changes in Regional Cerebral Protein Synthesis: AnIn VivoStudy in theFmr1Null Mouse
Qin, M., Kang, J., Burlin, T. V., Jiang, C., & Smith, C. B. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.0093-05.2005 · Cited by 263 · see citing works
“One of the mRNAs translated in dendrites in response to activation of metabotropic glutamate receptors (mGluRs) is fragile X mental retardation-1 (Fmr1) (Weiler et al., 1997).”
Background
Expression of microRNAs and their precursors in synaptic fractions of adult mouse forebrain
Lugli, G., Torvik, V. I., Larson, J., & Smalheiser, N. R. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05413.x · Cited by 261 · see citing works
The fragile X syndrome.
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
Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses
Antar, L. N., Li, C., Zhang, H., Carroll, R. C., & Bassell, G. J. (2006) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2006.02.001 · Cited by 259 · see citing works
“Activation of metabotropic glutamate receptors (mGluR) can stimulate the local synthesis of FMRP (Weiler et al., 1997) and also promote its trafficking from the soma into dendrites (Antar et al., 2004, 2005). mGluR activation is also associated with a protein-synthesis-dependent lengthening of…”
Background
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
“demonstrated that FMRP is synthesized following application of the receptor agonist DHPG (dihydroxyphenylglycine) in synaptoneurosomes (46).”
Local protein synthesis and its role in synapse-specific plasticity
Martin, K. C., Barad, M., & Kandel, E. R. (2000) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(00)00128-8 · Cited by 258 · see citing works
Dicer and eIF2c are enriched at postsynaptic densities in adult mouse brain and are modified by neuronal activity in a calpain‐dependent manner
Lugli, G., Larson, J., Martone, M. E., Jones, Y., & Smalheiser, N. R. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03224.x · Cited by 253 · see citing works
Reversal of Disease-Related Pathologies in the Fragile X Mouse Model by Selective Activation of GABA B Receptors with Arbaclofen
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
The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95
Todd, P. K., Mack, K. J., & Malter, J. S. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2336265100 · Cited by 280 · see citing works
Localization of FMRP‐associated mRNA granules and requirement of microtubules for activity‐dependent trafficking in hippocampal neurons
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
“…sequence and a nuclear export sequence (Bardoni et al. 1997; Eberhart et al. 1996), FMRP may play a role in the nucleocytoplasmic shuttling of mRNA (Feng et al. 1997b), dendritic mRNA localization (Miyashiro et al. 2003) or synaptic protein synthesis (Weiler et al. 1997; Zalfa et al. 2003).”
Background
Homer Interactions Are Necessary for Metabotropic Glutamate Receptor-Induced Long-Term Depression and Translational Activation
Ronesi, J. A., & Huber, K. M. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5019-07.2008 · Cited by 244 · see citing works
“Brief activation of group I metabotropic glutamate receptors (mGluRs) causes long-term functional changes at synapses via direct regulation of new protein synthesis (Weiler et al., 1997; Huber et al., 2000; Banko et al., 2006; Hou et al., 2006; Mameli et al., 2007; Muddashetty et al., 2007).”
Background
Fragile X mental retardation protein and synaptic plasticity
Sidorov, M. S., Auerbach, B. D., & Bear, M. F. (2013) · Molecular Brain · doi:10.1186/1756-6606-6-15 · Cited by 242 · see citing works
“Multiple experimental manipulations associated with synaptic plasticity have been shown to increase FMRP levels, including exposure to an enriched environment, a complex learning task, and pharmacological activation of group 1 metabotropic glutatmate receptors (mGluRs) [31,36-38].”
Background
Metabotropic Glutamate Receptors Trigger Homosynaptic Protein Synthesis to Prolong Long-Term Potentiation
Raymond, C. R., Thompson, V. L., Tate, W. P., & Abraham, W. C. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-03-00969.2000 · Cited by 239 · see citing works
“In confirmation of this, activation of mGluRs can trigger protein synthesis in hippocampal synaptoneurosome preparations, which contain no transcriptional machinery (Weiler and Greenough, 1993; Weiler et al., 1997).”
BackgroundMethod
Synaptic plasticity in cortical systems
Klintsova, A. Y., & Greenough, W. T. (1999) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(99)80028-2 · Cited by 237 · see citing works
Metabotropic Glutamate Receptor-Mediated Long-Term Depression: Molecular Mechanisms
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“A role for FMRP was indicated in mGluR-LTD when FMRP expression levels were enhanced upon mGluR activation (Weiler et al., 1997).”
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“As FMRP functions near synapses and may regulate activation-dependent dendritic translation (Weiler et al. 1997), it could certainly play a role in modulating specific forms of neuronal excitability, such as those active in generating the centrotemporal spikes pattern.”
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“2-fold enriched; and Fragile X mental retardation protein (FMRP) (Weiler et al., 1997), 3.”
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“associates with actively translating ribosomes in dendrites [6,7].”
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“Consistent (Feng et al., 1997; Weiler et al., 1997 ).”
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“Previous studies indicated that FMRP expression appears principally near synapses following neurotransmitter activation and that FMRP plays an important role in maturation and synaptic plasticity (Comery et al., 1997; Weiler et al., 1997; Weiler and Greenough, 1999; Irwin et al., 2000).”
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Identification of mRNA/Protein (mRNP) Complexes Containing Purα, mStaufen, Fragile X Protein, and Myosin Va and their Association with Rough Endoplasmic Reticulum Equipped with a Kinesin Motor
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Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses
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“Evidence suggests that FMRP is involved in mGluR-mediated synaptic plasticity (Huber et al., 2002; Laggerbauer et al., 2001; Weiler et al., 1997), and activation of mGluR increases translation of PSD-95 through an FMRP-mediated mechanism (Todd and Malter, 2002; Todd et al.”
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Autistic Behavior, FMR1 Protein, and Developmental Trajectories in Young Males with Fragile X Syndrome
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Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses
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
Untitled work
Miller (1999) · doi:10.1002/(sici)1096-8628(19990402)83:4
Metabotropic Glutamate Receptors and Fragile X Mental Retardation Protein: Partners in Translational Regulation at the Synapse
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Dysregulated Metabotropic Glutamate Receptor-Dependent Translation of AMPA Receptor and Postsynaptic Density-95 mRNAs at Synapses in a Mouse Model of Fragile X Syndrome
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The fragile X mental retardation protein–RNP granules show an mGluR-dependent localization in the post-synaptic spines
Ferrari, F., Mercaldo, V., Piccoli, G., Sala, C., Cannata, S. M., Achsel, T., & Bagni, C. (2007) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2006.11.015 · Cited by 122 · see citing works

Authors: 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.
Affiliations: University of Illinois Urbana-Champaign (US)
ORCID: Irwin, Scott A.
Klintsova, Anna Y.
Spencer, Corinne M.
Eberwine, James
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1997-05-13
Volume: 94
Issue: 10
Pages: 5395-5400
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.94.10.5395
PMC: PMC24689
OpenAlex: W2002760096
Cited by: 644
References: 58
Citations by year: 2026: 2 · 2025: 8 · 2024: 8 · 2023: 11 · 2022: 11 · 2021: 12 · 2020: 8 · 2019: 14 · 2018: 13 · 2017: 19 · 2016: 15 · 2015: 23 · 2014: 24 · 2013: 27 · 2012: 29
FWCI: 12.99
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: FRAXA Research Foundation (MH35321)
John D. and Catherine T. MacArthur Foundation
National Institutes of Health
U.S. Public Health Service
National Institute on Aging (AG10154, R01AG010154)
National Institute of Mental Health (MH-35321, R01MH035321, R37MH035321)
National Center for Research Resources (RR 04050, P41RR004050)
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: FMRP, local protein synthesis, metabotropic glutamate receptor 1, polysomes, synaptoneurosomes, dendritic mRNA, synapse maturation, synaptic plasticity, dendritic translation
MeSH terms: Amino Acid Sequence, Animals, Antibodies, Brain, Dendrites, Glycine, Humans, Kinetics, Molecular Sequence Data, Nerve Tissue Proteins, Neurons, Organ Specificity, Polyribosomes, Resorcinols, RNA, Messenger, Synapses, Protein Biosynthesis, Oligonucleotide Probes, Gene Library, Antisense Elements (Genetics), RNA-Binding Proteins, Sequence Homology, Amino Acid, DNA, Complementary, Receptors, Metabotropic Glutamate, Neurotransmitter Agents, Excitatory Amino Acid Antagonists, Rats, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1

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Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation

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