title: Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome.
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.
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, California 92697, USA.
authors.forename: Kwang-Mook
authors.initials: KM
authors.lastname: Jung
authors.forename: Marja
authors.initials: M
authors.lastname: Sepers
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Henstridge
authors.forename: Olivier
authors.initials: O
authors.lastname: Lassalle
authors.forename: Daniela
authors.initials: D
authors.lastname: Neuhofer
authors.forename: Henry
authors.initials: H
authors.lastname: Martin
authors.forename: Melanie
authors.initials: M
authors.lastname: Ginger
authors.forename: Andreas
authors.initials: A
authors.lastname: Frick
authors.forename: Nicholas V
authors.initials: NV
authors.lastname: DiPatrizio
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.forename: Istvan
authors.initials: I
authors.lastname: Katona
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Olivier J
authors.initials: OJ
authors.lastname: Manzoni
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism*; D005989:Glycerides / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D051860:Fragile X Messenger Ribonucleoprotein 1; D005989:Glycerides; D008071:Lipoprotein Lipase; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse; C094503:glyceryl 2-arachidonate