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

TY - JOUR

T1 - Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome

AU - Jung, Kwang-Mook

AU - Sepers, Marja

AU - Henstridge, Christopher M.

AU - Lassalle, Olivier

AU - Neuhofer, Daniela

AU - Martin, Henry

AU - Ginger, Melanie

AU - Frick, Andreas

AU - DiPatrizio, Nicholas V.

AU - Mackie, Ken

AU - Katona, Istvan

AU - Piomelli, Daniele

AU - Manzoni, Olivier J.

N1 - M1 - 1080

PY - 2012/9/25

Y1 - 2012/9/25

N2 - 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.

AB - 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.

KW - METABOTROPIC GLUTAMATE RECEPTORS

KW - DIACYLGLYCEROL-LIPASE-ALPHA

KW - MENTAL-RETARDATION PROTEIN

KW - LONG-TERM DEPRESSION

KW - NUCLEUS-ACCUMBENS

KW - SYNAPTIC PLASTICITY

KW - MONOGLYCERIDE LIPASE

KW - MESSENGER-RNAS

KW - CB1 RECEPTOR

KW - TRANSLATION

U2 - 10.1038/ncomms2045

DO - 10.1038/ncomms2045

M3 - Article

SN - 2041-1723

VL - 3

JO - Nature Communications

JF - Nature Communications

ER -