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

Kwang-Mook Jung, Marja Sepers, Christopher M. Henstridge, Olivier Lassalle, Daniela Neuhofer, Henry Martin, Melanie Ginger, Andreas Frick, Nicholas V. DiPatrizio, Ken Mackie, Istvan Katona, Daniele Piomelli, Olivier J. Manzoni

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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-alpha (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.
Original languageEnglish
Number of pages11
JournalNature Communications
Volume3
DOIs
Publication statusPublished - 25 Sep 2012

Keywords

  • METABOTROPIC GLUTAMATE RECEPTORS
  • DIACYLGLYCEROL-LIPASE-ALPHA
  • MENTAL-RETARDATION PROTEIN
  • LONG-TERM DEPRESSION
  • NUCLEUS-ACCUMBENS
  • SYNAPTIC PLASTICITY
  • MONOGLYCERIDE LIPASE
  • MESSENGER-RNAS
  • CB1 RECEPTOR
  • TRANSLATION

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    Jung, K-M., Sepers, M., Henstridge, C. M., Lassalle, O., Neuhofer, D., Martin, H., Ginger, M., Frick, A., DiPatrizio, N. V., Mackie, K., Katona, I., Piomelli, D., & Manzoni, O. J. (2012). Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nature Communications, 3. https://doi.org/10.1038/ncomms2045