Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome

Nat Commun. 2012;3:1080. doi: 10.1038/ncomms2045.

Abstract

Fragile X syndrome, the most commonly known genetic cause of autism, is due to loss of the fragile X mental retardation protein, which regulates signal transduction at metabotropic glutamate receptor-5 in the brain. Fragile X mental retardation protein deletion in mice enhances metabotropic glutamate receptor-5-dependent long-term depression in the hippocampus and cerebellum. Here we show that a distinct type of metabotropic glutamate receptor-5-dependent long-term depression at excitatory synapses of the ventral striatum and prefrontal cortex, which is mediated by the endocannabinoid 2-arachidonoyl-sn-glycerol, is absent in fragile X mental retardation protein-null mice. In these mutants, the macromolecular complex that links metabotropic glutamate receptor-5 to the 2-arachidonoyl-sn-glycerol-producing enzyme, diacylglycerol lipase-α (endocannabinoid signalosome), is disrupted and metabotropic glutamate receptor-5-dependent 2-arachidonoyl-sn-glycerol formation is compromised. These changes are accompanied by impaired endocannabinoid-dependent long-term depression. Pharmacological enhancement of 2-arachidonoyl-sn-glycerol signalling normalizes this synaptic defect and corrects behavioural abnormalities in fragile X mental retardation protein-deficient mice. The results identify the endocannabinoid signalosome as a molecular substrate for fragile X syndrome, which might be targeted by therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acids / metabolism*
  • Endocannabinoids / metabolism*
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / metabolism*
  • Glycerides / metabolism*
  • Lipoprotein Lipase / genetics
  • Lipoprotein Lipase / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology

Substances

  • Arachidonic Acids
  • Endocannabinoids
  • Fmr1 protein, mouse
  • Glycerides
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Fragile X Mental Retardation Protein
  • glyceryl 2-arachidonate
  • Lipoprotein Lipase