Increased Threshold for Spike-Timing-Dependent Plasticity Is Caused by Unreliable Calcium Signaling in Mice Lacking Fragile X Gene Fmr1
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Fragile X syndrome, caused by a mutation in the Fmr1 gene, is characterized by mental retardation. Several studies reported the absence of long-term potentiation (LTP) at neocortical synapses in Fmr1 knockout (FMR1-KO) mice, but underlying cellular mechanisms are unknown. We find that in the prefrontal cortex (PFC) of FMR1-KO mice, spike-timing-dependent LTP (tLTP) is not so much absent, but rather, the threshold for tLTP induction is increased. Calcium signaling in dendrites and spines is compromised. First, dendrites and spines more often fail to show calcium transients. Second, the activity of L-type calcium channels is absent in spines. tLTP could be restored by improving reliability and amplitude of calcium signaling by increasing neuronal activity. In FMR1-KO mice that were raised in enriched environments, tLTP was restored to WT levels. Our results show that mechanisms for synaptic plasticity are in place in the FMR1-KO mouse PFC, but require stronger neuronal activity to be triggered.
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In the FXS mouse model, an enriched environment reduces multiple cellular and behavioral deficits.
“an enriched environment has been reported to ameliorate several cellular and behavioral deficits in the mouse model for FXS (129, 130).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [130]
Cites
Bi, G.-Q., & Poo, M.-M. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-24-10464.1998 · Cited by 4,744 · see citing works
Regulation of Synaptic Efficacy by Coincidence of Postsynaptic APs and EPSPs
Markram, H., Lübke, J., Frotscher, M., & Sakmann, B. (1997) · Science · doi:10.1126/science.275.5297.213 · Cited by 3,832 · see citing works
Long-Term Potentiation--A Decade of Progress?
Malenka, R. C., & Nicoll, A. R. A. (1999) · Science · doi:10.1126/science.285.5435.1870 · Cited by 2,729 · see citing works
Neural consequences of enviromental enrichment
van Praag, H., Kempermann, G., & Gage, F. H. (2000) · Nature Reviews Neuroscience · doi:10.1038/35044558 · Cited by 2,468 · see citing works
Enriched environments, experience-dependent plasticity and disorders of the nervous system
Nithianantharajah, J., & Hannan, A. J. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1970 · Cited by 1,771 · 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
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
A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory.
Lisman, J. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.23.9574 · Cited by 1,127 · see citing works
Fmr1 knockout mice: A model to study fragile X mental retardation
THEDUTCHBELGIANFRAGILEXCONSOR (1994) · Cell · doi:10.1016/0092-8674(94)90569-x · Cited by 1,075 · see citing works
Abnormal dendritic spines in fragile X knockout mice: Maturation and pruning deficits
Comery, T. A., Harris, J. B., Willems, P. J., Oostra, B. A., Irwin, S. A., Weiler, I. J., & Greenough, W. T. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.10.5401 · Cited by 1,046 · see citing works
Postsynaptic Calcium Is Sufficient for Potentiation of Hippocampal Synaptic Transmission
Malenka, R. C., Kauer, J. A., Zucker, R. S., & Nicoll, R. A. (1988) · Science · doi:10.1126/science.2845577 · Cited by 829 · see citing works
The Life Cycle of Ca2+ Ions in Dendritic Spines
Sabatini, B. L., Oertner, T. G., & Svoboda, K. (2002) · Neuron · doi:10.1016/s0896-6273(02)00573-1 · Cited by 745 · see citing works
Zalfa, F., Giorgi, M., Primerano, B., Moro, A., Di Penta, A., Reis, S., Oostra, B., & Bagni, C. (2003) · Cell · doi:10.1016/s0092-8674(03)00079-5 · Cited by 676 · see citing works
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 · see citing works
Abnormal Development of Dendritic Spines in<i>FMR1</i>Knock-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
Analysis of neocortex in three males with the Fragile X syndrome
Hinton, V. J., Brown, W. T., Wisniewski, K., & Rudelli, R. D. (1991) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320410306 · Cited by 527 · see citing works
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
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
Spine Ca<sup>2+</sup>Signaling in Spike-Timing-Dependent Plasticity
Nevian, T., & Sakmann, B. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1749-06.2006 · Cited by 458 · 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
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
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
Characterization and localization of the FMR-1 gene product associated with fragile X syndrome
Verheij, C., Bakker, C. E., de Graaff, E., Keulemans, J., Willemsen, R., Verkerk, A. J. M. H., Galjaard, H., Reuser, A. J. J., Hoogeveen, A. T., & Oostra, B. A. (1993) · Nature · doi:10.1038/363722a0 · Cited by 343 · see citing works
Koester, H. J., & Sakmann, B. J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.16.9596 · Cited by 338 · see citing works
Restivo, L., Ferrari, F., Passino, E., Sgobio, C., Bock, J., Oostra, B. A., Bagni, C., & Ammassari-Teule, M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504984102 · Cited by 299 · see citing works
Koester, H. J., & Sakmann, B. (2000) · The Journal of Physiology · doi:10.1111/j.1469-7793.2000.00625.x · Cited by 288 · see citing works
Analysis of calcium channels in single spines using optical fluctuation analysis
Sabatini, B. L., & Svoboda, K. (2000) · Nature · doi:10.1038/35046076 · Cited by 269 · 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
Deficits in trace fear memory and long-term potentiation in a mouse model for fragile X syndrome
Zhao, M.-G., Toyoda, H., Ko, S. W., Ding, H.-K., Wu, L.-J., & Zhuo, M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1520-05.2005 · Cited by 258 · see citing works
Couey, J. J., Meredith, R. M., Spijker, S., Poorthuis, R. B., Smit, A. B., Brussaard, A. B., & Mansvelder, H. D. (2007) · Neuron · doi:10.1016/j.neuron.2007.03.006 · Cited by 253 · see citing works
Self-citationSchiller, J., Schiller, Y., & Clapham, D. E. (1998) · Nature Neuroscience · doi:10.1038/363 · Cited by 231 · see citing works
Spike timing, calcium signals and synaptic plasticity
Sjöström, P. (2002) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(02)00325-2 · Cited by 231 · see citing works
Galvez, R., & Greenough, W. T. (2005) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.30709 · Cited by 231 · see citing works
Weiler, I. J., Spangler, C. C., Klintsova, A. Y., Grossman, A. W., Kim, S. H., Bertaina-Anglade, V., Khaliq, H., de Vries, F. E., Lambers, F. A. E., Hatia, F., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407533101 · Cited by 210 · see citing works
Grossman, A. W., Elisseou, N. M., McKinney, B. C., & Greenough, W. T. (2006) · Brain Research · doi:10.1016/j.brainres.2006.02.044 · Cited by 204 · see citing works
Dendritic spine abnormalities in the occipital cortex of C57BL/6Fmr1 knockout mice
McKinney, B. C., Grossman, A. W., Elisseou, N. M., & Greenough, W. T. (2005) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30183 · Cited by 184 · see citing works
Chen, L., Yun, S.-W., Seto, J., Liu, W., & Toth, M. (2003) · Neuroscience · doi:10.1016/s0306-4522(03)00406-8 · Cited by 160 · see citing works
Meredith, R. M., Floyer-Lea, A., & Paulsen, O. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-35-11142.2003 · Cited by 158 · see citing works
Self-citationVolk, L. J., Daly, C. A., & Huber, K. M. (2006) · Journal of Neurophysiology · doi:10.1152/jn.00383.2005 · Cited by 150 · see citing works
Of mice and the fragile X syndrome
Kooy, R. F. (2003) · Trends in Genetics · doi:10.1016/s0168-9525(03)00017-9 · Cited by 134 · see citing works
B, T. J. S. A. (1999) · Neuron · doi:10.1016/s0896-6273(00)81025-9 · Cited by 108 · see citing works
Early Postnatal Plasticity in Neocortex of <i>Fmr1</i> Knockout Mice
Desai, N. S., Casimiro, T. M., Gruber, S. M., & Vanderklish, P. W. (2006) · Journal of Neurophysiology · doi:10.1152/jn.00221.2006 · Cited by 92 · see citing works
The fragile X–cerebellum connection
Huber, K. M. (2006) · Trends in Neurosciences · doi:10.1016/j.tins.2006.02.001 · Cited by 47 · see citing works
Discourse Processing in Women with Fragile X Syndrome: Evidence for a Deficit Establishing Coherence
Simon, J. A., Keenan, J. M., Pennington, B. F., Taylor, A. K., & Hagerman, R. J. (2001) · Cognitive Neuropsychology · doi:10.1080/02643290126042 · Cited by 40 · see citing works
Voltage-Activated Currents through Calcium Channels in Rat Pituitary Melanotrophic Cells
Keja, J. A., Stoof, J. C., & Kits, K. S. (2008) · Neuroendocrinology · doi:10.1159/000125741 · Cited by 28 · see citing works
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Regulation of Synaptic Structure and Function by FMRP-Associated MicroRNAs miR-125b and miR-132
Edbauer, D., Neilson, J. R., Foster, K. A., Wang, C.-F., Seeburg, D. P., Batterton, M. N., Tada, T., Dolan, B. M., Sharp, P. A., & Sheng, M. (2010) · Neuron · doi:10.1016/j.neuron.2010.01.005 · Cited by 735 · see citing works
Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC
Jeon, D., Kim, S., Chetana, M., Jo, D., Ruley, H. E., Lin, S.-Y., Rabah, D., Kinet, J.-P., & Shin, H.-S. (2010) · Nature Neuroscience · doi:10.1038/nn.2504 · Cited by 651 · see citing works
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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
Critical period plasticity is disrupted in the barrel cortex of FMR1 knockout mice
Harlow, E. G., Till, S. M., Russell, T. A., Wijetunge, L. S., Kind, P., & Contractor, A. (2010) · Neuron · doi:10.1016/j.neuron.2010.01.024 · Cited by 252 · see citing works
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Verhoog, M. B., Goriounova, N. A., Obermayer, J., Stroeder, J., Hjorth, J. J. J., Testa-Silva, G., Baayen, J. C., de Kock, C. P. J., Meredith, R. M., & Mansvelder, H. D. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.3158-13.2013 · Cited by 127 · see citing works
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Zang, J. B., Nosyreva, E. D., Spencer, C. M., Volk, L. J., Musunuru, K., Zhong, R., Stone, E. F., Yuva-Paylor, L. A., Huber, K. M., Paylor, R., et al. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000758 · Cited by 138 · see citing works
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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 · see citing works
El Bekay, R., Romero‐Zerbo, Y., Decara, J., Sanchez‐Salido, L., Del Arco‐Herrera, I., Rodríguez‐de Fonseca, F., & De Diego‐Otero, Y. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05939.x · Cited by 85 · see citing works
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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
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- Authors
- Meredith, R. M., Holmgren, C. D., Weidum, M., Burnashev, N., & Mansvelder, H. D.
- Affiliations
- Vrije Universiteit Amsterdam (NL)
- Corresponding author
- Burnashev, Nail
- Mansvelder, Huibert D.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2007-05
- Volume
- 54
- Issue
- 4
- Pages
- 627-638
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2045203721
- Cited by
- 190
- References
- 45
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 24 · 2022: 3 · 2021: 10 · 2020: 8 · 2019: 12 · 2018: 7 · 2017: 13 · 2016: 7 · 2015: 8 · 2014: 17 · 2013: 13 · 2012: 10
- FWCI
- 6.96
- 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, 2269 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)
- VU Research Portal (publishedVersion, other-oa)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- 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 › Memory and Neural Mechanisms
- Keywords
- fragile X syndrome, Fmr1 knockout mice, spike-timing-dependent plasticity, long-term potentiation, calcium signaling, dendritic calcium transients, dendritic spines, L-type calcium channels, prefrontal cortex, synaptic plasticity, environmental enrichment, neuronal activity
- MeSH terms
- Action Potentials, Animals, Animals, Newborn, Calcium, Calcium Channel Blockers, Cerebral Cortex, Electric Stimulation, Environment, Female, Male, Mice, Inbred C57BL, Neuronal Plasticity, Nifedipine, Time Factors, Pyramidal Cells, Mice, Knockout, Patch-Clamp Techniques, Excitatory Postsynaptic Potentials, Calcium Signaling, Dendritic Spines, Mice, Fragile X Messenger Ribonucleoprotein 1, In Vitro Techniques
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