FMRP Acts as a Key Messenger for Dopamine Modulation in the Forebrain
Open accessAbstract
The fragile X mental retardation protein (FMRP) is an RNA-binding protein that controls translational efficiency and regulates synaptic plasticity. Here, we report that FMRP is involved in dopamine (DA) modulation of synaptic potentiation. AMPA glutamate receptor subtype 1 (GluR1) surface expression and phosphorylation in response to D1 receptor stimulation were reduced in cultured Fmr1(-/-) prefrontal cortex (PFC) neurons. Furthermore, D1 receptor signaling was impaired, accompanied by D1 receptor hyperphosphorylation at serine sites and subcellular redistribution of G protein-coupled receptor kinase 2 (GRK2) in both PFC and striatum of Fmr1(-/-) mice. FMRP interacted with GRK2, and pharmacological inhibition of GRK2 rescued D1 receptor signaling in Fmr1(-/-) neurons. Finally, D1 receptor agonist partially rescued hyperactivity and enhanced the motor function of Fmr1(-/-) mice. Our study has identified FMRP as a key messenger for DA modulation in the forebrain and may provide insights into the cellular and molecular mechanisms underlying fragile X syndrome.
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In studies of FMR1 mutant mice, Zhuo and colleagues reported that cortical and striatal neurons from the mutant mice exhibit abnormal D1 receptor signaling and disrupted synaptic plasticity in response to D1 receptor activation.
“In studies of FMR1 mutant mice, Zhuo and colleagues reported that cortical and striatal neurons from the mutant mice exhibit abnormal D1 receptor signaling and disrupted synaptic plasticity in response to D1 receptor activation.”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [715]
These neuronal deficits could be rescued by restoring the FMR1 gene to the mutant neurons.
“Remarkably, these neuronal deficits could be rescued by restoring the FMR1 gene to the mutant neurons [715].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [715]
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References 65 · Cited by 186
- Authors
- Wang, H., Wu, L.-J., Kim, S. S., Lee, F. J. S., Gong, B., Toyoda, H., Ren, M., Shang, Y.-Z., Xu, H., Liu, F., Zhao, M.-G., & Zhuo, M.
- Affiliations
- University of Toronto (CA)
- Centre for Addiction and Mental Health (CA)
- Corresponding author
- Zhao, Ming-Gao
- Zhuo, Min
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 59
- Issue
- 4
- Pages
- 634-647
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2012888336
- Cited by
- 186
- References
- 65
- Citations by year
- 2025: 2 · 2024: 4 · 2023: 9 · 2022: 11 · 2021: 8 · 2020: 16 · 2019: 3 · 2018: 3 · 2017: 10 · 2016: 9 · 2015: 19 · 2014: 11 · 2013: 15 · 2012: 20
- FWCI
- 8.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (30670684)
- Canadian Institutes of Health Research
- 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 › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- FMRP, fragile X syndrome, dopaminergic modulation, GRK2, GluR1, synaptic potentiation, prefrontal cortex, striatum, translational regulation, hyperactivity, motor function
- MeSH terms
- Animals, Cells, Cultured, Dopamine, Male, Synaptic Transmission, Neurons, Psychomotor Performance, Prefrontal Cortex, Receptors, Dopamine D1, Long-Term Potentiation, Receptors, AMPA, Mice, Knockout, Mice, Fragile X Messenger Ribonucleoprotein 1, G-Protein-Coupled Receptor Kinase 2
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