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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    209 Citations (Scopus)
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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 Sept 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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