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-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.

Original languageEnglish
Article number1080
JournalNature communications
Volume3
DOIs
Publication statusPublished - Oct 8 2012

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

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, [1080]. https://doi.org/10.1038/ncomms2045