Abnormal mGlu 5 receptor/endocannabinoid coupling in mice lacking FMRP and BC1 RNA

Neuropsychopharmacology. 2010 Jun;35(7):1500-9. doi: 10.1038/npp.2010.19. Epub 2010 Mar 10.


Transcriptional silencing of the gene encoding the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP acts as a translational repressor at central synapses, and molecular and synaptic plasticity studies have shown that the absence of this protein alters metabotropic glutamate 5 receptors (mGlu5Rs)-mediated signaling. In the striatum of mice lacking FMRP, we found enhanced activity of diacylglycerol lipase (DAGL), the enzyme limiting 2-arachidonoylglicerol (2-AG) synthesis, associated with altered sensitivity of GABA synapses to the mobilization of this endocannabinoid by mGlu5R stimulation with DHPG. Mice lacking another repressor of synaptic protein synthesis, BC1 RNA, also showed potentiated mGlu5R-driven 2-AG responses, indicating that both FMRP and BC1 RNA act as physiological constraints of mGlu5R/endocannabinoid coupling at central synapses. The effects of FMRP ablation on DAGL activity and on DHPG-mediated inhibition of GABA synapses were enhanced by simultaneous genetic inactivation of FMRP and BC1 RNA. In double FMRP and BC1 RNA lacking mice, striatal levels of 2-AG were also enhanced compared with control animals and to single mutants. Our data indicate for the first time that mGlu5R-driven endocannabinoid signaling in the striatum is under the control of both FMRP and BC1 RNA. The abnormal mGlu5R/2-AG coupling found in FMRP-KO mice emphasizes the involvement of mGlu5Rs in the synaptic defects of FXS, and identifies the modulation of the endocannabinoid system as a novel target for the treatment of this severe neuropsychiatric disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acids / metabolism
  • Cannabinoid Receptor Modulators / metabolism*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Corpus Striatum / physiology
  • Dronabinol / analogs & derivatives
  • Dronabinol / pharmacology
  • Endocannabinoids*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Fragile X Mental Retardation Protein / genetics*
  • Gene Expression Regulation / genetics*
  • Glycerides / metabolism
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / genetics
  • Lipoprotein Lipase / metabolism
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Mice
  • Mice, Knockout
  • Patch-Clamp Techniques / methods
  • Piperidines / pharmacology
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Pyrazoles / pharmacology
  • RNA, Small Cytoplasmic / genetics*
  • Receptors, Kainic Acid / metabolism*
  • Statistics, Nonparametric


  • Arachidonic Acids
  • BC1 RNA
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Excitatory Amino Acid Antagonists
  • Fmr1 protein, mouse
  • Gluk1 kainate receptor
  • Glycerides
  • Piperidines
  • Pyrazoles
  • RNA, Small Cytoplasmic
  • Receptors, Kainic Acid
  • Fragile X Mental Retardation Protein
  • AM 251
  • Methoxyhydroxyphenylglycol
  • Dronabinol
  • glyceryl 2-arachidonate
  • Lipoprotein Lipase
  • HU 211
  • 3,4-dihydroxyphenylglycol