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

• Published in: Nature communications Vol. 3; no. 1; p. 1080
• Main Authors: Jung, Kwang-Mook, Sepers, Marja, Henstridge, Christopher M., Lassalle, Olivier, Neuhofer, Daniela, Martin, Henry, Ginger, Melanie, Frick, Andreas, DiPatrizio, Nicholas V., Mackie, Ken, Katona, Istvan, Piomelli, Daniele, Manzoni, Olivier J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.09.2012; Nature Publishing Group; Nature Pub. Group
• Subjects: 631/208/2489/144; 631/378/340; 692/699/476; 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; Humanities and Social Sciences; Life Sciences; Lipoprotein Lipase - genetics; Lipoprotein Lipase - metabolism; Male; Mice; Mice, Knockout; multidisciplinary; Neurobiology; Neurons and Cognition; Pharmaceutical sciences; Pharmacology; Psychology and behavior; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate - genetics; Receptors, Metabotropic Glutamate - metabolism; Science; Science (multidisciplinary); Signal Transduction - genetics; Signal Transduction - physiology; Molecular neuroscience; Psychiatric disorders; Disease genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2045

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. Fragile X syndrome is a major genetic cause of autism and is caused by loss of the fragile X mental retardation protein. In a mouse model of fragile X syndrome, Jung et al . show that an absence of neuronal endocannabinoid signalling is responsible for the neurophysiological and behavioural defects.