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.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S1A8, Canada.
authors.forename: Hansen
authors.initials: H
authors.lastname: Wang
authors.forename: Long-Jun
authors.initials: LJ
authors.lastname: Wu
authors.forename: Susan S
authors.initials: SS
authors.lastname: Kim
authors.forename: Frank J S
authors.initials: FJ
authors.lastname: Lee
authors.forename: Bo
authors.initials: B
authors.lastname: Gong
authors.forename: Hiroki
authors.initials: H
authors.lastname: Toyoda
authors.forename: Ming
authors.initials: M
authors.lastname: Ren
authors.forename: Yu-Ze
authors.initials: YZ
authors.lastname: Shang
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Ming-Gao
authors.initials: MG
authors.lastname: Zhao
authors.forename: Min
authors.initials: M
authors.lastname: Zhuo