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

Kwang-Mook Jung (1) , Marja Sepers (2, 3) , Christopher Henstridge (4) , Olivier Lassalle (5) , Daniela Neuhofer (5) , Henry Martin (5) , Melanie Ginger (3) , Andreas Frick (3) , Nicholas Dipatrizio (1) , Ken Mackie (6) , István Katona (4) , Daniele Piomelli (1) , Olivier Manzoni (5)

1 UC - University of California
2 Department of Psychiatry
3 Physiopathologie du système nerveux central - Institut François Magendie
4 MTA - Hungarian Academy of Sciences
5 INMED - INSERM U901 - Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université]
6 Indiana University [Bloomington]

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.

Mots clés: Disease genetics; Molecular neuroscience; Psychiatric disorders

Domaines: Neurobiologie; Pharmacologie; Psychologie et comportements

Kwang-Mook Jung, Marja Sepers, Christopher Henstridge, Olivier Lassalle, Daniela Neuhofer, et al.. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nature Communications, 2012, 3 (1), ⟨10.1038/ncomms2045⟩. ⟨hal-01826158⟩