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

Neuron. 2008 Aug 28;59(4):634-47. doi: 10.1016/j.neuron.2008.06.027.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Dopamine / metabolism*
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism*
  • G-Protein-Coupled Receptor Kinase 2 / metabolism
  • Long-Term Potentiation / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Neurons / metabolism*
  • Prefrontal Cortex / cytology
  • Prefrontal Cortex / metabolism*
  • Psychomotor Performance / physiology
  • Receptors, AMPA / metabolism
  • Receptors, Dopamine D1 / agonists
  • Receptors, Dopamine D1 / metabolism
  • Synaptic Transmission / physiology

Substances

  • Fmr1 protein, mouse
  • Receptors, AMPA
  • Receptors, Dopamine D1
  • Fragile X Mental Retardation Protein
  • GRK2 protein, mouse
  • G-Protein-Coupled Receptor Kinase 2
  • glutamate receptor ionotropic, AMPA 1
  • Dopamine