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 () and Olivier J. Manzoni ()
Additional contact information
Kwang-Mook Jung: University of California
Marja Sepers: INSERM U862, Circuit and Dendritic Mechanisms Underlying Cortical Plasticity Group, Neurocentre Magendie, 146 Rue Léo-Saignat, F 33077 Bordeaux Cedex, France.
Christopher M. Henstridge: Institute of Experimental Medicine, Hungarian Academy of Sciences
Olivier Lassalle: INSERM U901
Daniela Neuhofer: INSERM U901
Henry Martin: INSERM U901
Melanie Ginger: INSERM U862, Circuit and Dendritic Mechanisms Underlying Cortical Plasticity Group, Neurocentre Magendie, 146 Rue Léo-Saignat, F 33077 Bordeaux Cedex, France.
Andreas Frick: INSERM U862, Circuit and Dendritic Mechanisms Underlying Cortical Plasticity Group, Neurocentre Magendie, 146 Rue Léo-Saignat, F 33077 Bordeaux Cedex, France.
Nicholas V. DiPatrizio: University of California
Ken Mackie: Gill Center for Biomolecular Science, Indiana University
Istvan Katona: Institute of Experimental Medicine, Hungarian Academy of Sciences
Daniele Piomelli: University of California
Olivier J. Manzoni: INSERM U862, Circuit and Dendritic Mechanisms Underlying Cortical Plasticity Group, Neurocentre Magendie, 146 Rue Léo-Saignat, F 33077 Bordeaux Cedex, France.

Nature Communications, 2012, vol. 3, issue 1, 1-11

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms2045

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