Fragile X Mental Retardation Protein Is Required for Synapse Elimination by the Activity-Dependent Transcription Factor MEF2
Open accessAbstract
Fragile X syndrome (FXS), the most common genetic form of mental retardation and autism, is caused by loss-of-function mutations in an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP). Neurons from patients and the mouse Fmr1 knockout (KO) model are characterized by an excess of dendritic spines, suggesting a deficit in excitatory synapse elimination. In response to neuronal activity, myocyte enhancer factor 2 (MEF2) transcription factors induce robust synapse elimination. Here, we demonstrate that MEF2 activation fails to eliminate functional or structural excitatory synapses in hippocampal neurons from Fmr1 KO mice. Similarly, inhibition of endogenous MEF2 increases synapse number in wild-type but not Fmr1 KO neurons. MEF2-dependent synapse elimination is rescued in Fmr1 KO neurons by acute postsynaptic expression of wild-type but not RNA-binding mutants of FMRP. Our results reveal that active MEF2 and FMRP function together in an acute, cell-autonomous mechanism to eliminate excitatory synapses.
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Alterations of neuronal maturation are associated with neurodevelopmental disorders.
“alterations of neuronal maturation are associated with neurodevelopmental disorders”
From Xenotransplanted human cortical neurons reveal species-specific development and functional integration into mouse visual circuits (2019) · cites this paper as Pfeiffer et al., 2010
MEF2-mediated transcription and local FMRP-regulated translation work together to eliminate excitatory synapses.
“Huber and colleagues showed that MEF2-mediated transcription and local FMRP-regulated translation work together to eliminate excitatory synapses.”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Pfeiffer et al., 2010
In synapses with exaggerated LTD, as in FXS, LTD is linked to synapse elimination via the nuclear transcription factor MEF2.
“In synapses with exaggerated LTD, as in FXS, LTD is further linked to synapse elimination via the involvement of the nuclear transcription factor MEF2 (Pfeiffer et al., 2010).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Pfeiffer et al., 2010
The effects of MEF2 on synapse number may depend on FMRP.
“suggesting that the effects of MEF2 on synapse number may be FMRP dependent64.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [64]
Activation of MEF2 decreases the number of excitatory synapses in wild-type neurons but not in Fmr1 knockout neurons.
“activation of MEF2 leads to a decrease in the number of excitatory synapses in wild-type neurons, but not in Fmr1 knockout neurons”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [64]
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References 46 · Cited by 153
- Authors
- Pfeiffer, B. E., Zang, T., Wilkerson, J. R., Taniguchi, M., Maksimova, M. A., Smith, L. N., Cowan, C. W., & Huber, K. M.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Cowan, Christopher W.
- Huber, Kimberly M.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 66
- Issue
- 2
- Pages
- 191-197
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2864778
- OpenAlex
- W2059208184
- Cited by
- 153
- References
- 46
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 9 · 2023: 6 · 2022: 6 · 2021: 9 · 2020: 8 · 2019: 10 · 2018: 6 · 2017: 10 · 2016: 14 · 2015: 11 · 2014: 15 · 2013: 21 · 2012: 11
- FWCI
- 8.01
- 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, 1239 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)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Drug Abuse (DA 08227, T32DA007290, P01DA008227, F32DA027265)
- National Eye Institute (R01EY018207)
- National Institute of Neurological Disorders and Stroke (R01NS045711, NS045711, F31NS050992)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD052731, HD-052731)
- 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 Research and Splicing
- Keywords
- FMRP, MEF2, synaptic pruning, excitatory synapses, dendritic spines, Fmr1 knockout mice, hippocampal neurons, activity-dependent transcription, RNA-binding proteins, autism spectrum disorder, intellectual disability
- MeSH terms
- Animals, Hippocampus, Nerve Net, Neuronal Plasticity, Neurons, Organ Culture Techniques, Synapses, Transcription, Genetic, Transfection, RNA-Binding Proteins, Myogenic Regulatory Factors, Mice, Knockout, Patch-Clamp Techniques, Excitatory Postsynaptic Potentials, Microscopy, Fluorescence, Multiphoton, Dendritic Spines, Mice, Fragile X Messenger Ribonucleoprotein 1, Miniature Postsynaptic Potentials, MEF2 Transcription Factors
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