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

Research output: Contribution to journalArticle

124 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 languageEnglish (US)
Pages (from-to)634-647
Number of pages14
JournalNeuron
Volume59
Issue number4
DOIs
StatePublished - Aug 28 2008

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Keywords

  • HUMDISEASE
  • MOLNEURO

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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. (2008). FMRP Acts as a Key Messenger for Dopamine Modulation in the Forebrain. Neuron, 59(4), 634-647. https://doi.org/10.1016/j.neuron.2008.06.027