FMRP Acts as a Key Messenger for Dopamine Modulation in the Forebrain

Hansen Wang; Long Jun Wu; Susan S. Kim; Frank J.S. Lee; Bo Gong; Hiroki Toyoda; Ming Ren; Yu Ze Shang; Hui Xu; Fang Liu; Ming Gao Zhao; Min Zhuo

doi:10.1016/j.neuron.2008.06.027

FMRP Acts as a Key Messenger for Dopamine Modulation in the Forebrain

Hansen Wang, Long Jun Wu, Susan S. Kim, Frank J.S. Lee, Bo Gong, Hiroki Toyoda, Ming Ren, Yu Ze Shang, Hui Xu, Fang Liu, Ming Gao Zhao, Min Zhuo

Neurology

Research output: Contribution to journal › Article › peer-review

134 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	634-647
Number of pages	14
Journal	Neuron
Volume	59
Issue number	4
DOIs	https://doi.org/10.1016/j.neuron.2008.06.027
State	Published - Aug 28 2008

Keywords

HUMDISEASE
MOLNEURO

ASJC Scopus subject areas

Neuroscience(all)

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10.1016/j.neuron.2008.06.027

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@article{02ea52de4c9e49a6af3fa6c67457c942,

title = "FMRP Acts as a Key Messenger for Dopamine Modulation in the Forebrain",

abstract = "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.",

keywords = "HUMDISEASE, MOLNEURO",

author = "Hansen Wang and Wu, {Long Jun} and Kim, {Susan S.} and Lee, {Frank J.S.} and Bo Gong and Hiroki Toyoda and Ming Ren and Shang, {Yu Ze} and Hui Xu and Fang Liu and Zhao, {Ming Gao} and Min Zhuo",

note = "Funding Information: This work was supported by grants from the EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health, CIHR operating grants CIHR66975 and CIHR84256, Canada Research Chair, and NeuroCanada to M.Z. and National Natural Science Foundation of China (30670684) to M-G.Z. H.W., L-J.W., and M.-G.Z. were supported by postdoctoral fellowships from the Fragile X Research Foundation of Canada. We thank W.T. Greenough for his generous gift of Fmr1 WT and KO breeding pairs and J. Darnell for kindly providing the FMRP constructs. ",

year = "2008",

month = aug,

day = "28",

doi = "10.1016/j.neuron.2008.06.027",

language = "English (US)",

volume = "59",

pages = "634--647",

journal = "Neuron",

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TY - JOUR

T1 - FMRP Acts as a Key Messenger for Dopamine Modulation in the Forebrain

AU - Wang, Hansen

AU - Wu, Long Jun

AU - Kim, Susan S.

AU - Lee, Frank J.S.

AU - Gong, Bo

AU - Toyoda, Hiroki

AU - Ren, Ming

AU - Shang, Yu Ze

AU - Xu, Hui

AU - Liu, Fang

AU - Zhao, Ming Gao

AU - Zhuo, Min

N1 - Funding Information: This work was supported by grants from the EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health, CIHR operating grants CIHR66975 and CIHR84256, Canada Research Chair, and NeuroCanada to M.Z. and National Natural Science Foundation of China (30670684) to M-G.Z. H.W., L-J.W., and M.-G.Z. were supported by postdoctoral fellowships from the Fragile X Research Foundation of Canada. We thank W.T. Greenough for his generous gift of Fmr1 WT and KO breeding pairs and J. Darnell for kindly providing the FMRP constructs.

PY - 2008/8/28

Y1 - 2008/8/28

N2 - 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.

AB - 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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KW - MOLNEURO

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JO - Neuron

JF - Neuron

IS - 4

ER -

FMRP Acts as a Key Messenger for Dopamine Modulation in the Forebrain

Abstract

Keywords

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