The Fragile Nature of Endocannabinoid Signalling in Fragile X Syndrome

摘要: Fragile X Syndrome (FXS) is the most common form of inherited mental retardation and is caused by genetic silencing of the fmr1 gene, resulting in loss of the fragile X mental retardation protein (FMRP). The “mGlu-Theory” of FXS states that enhanced group I metabotropic glutamate receptor (mGlu) activity may explain the phenotypic manifestation of FXS. Glutamatergic synapses in the nucleus accumbens express a form of long term depression (LTD) requiring endocannabinoid (eCB) production via activation of postsynaptic mGlu5 receptors and their coupling to diacylglycerol lipase-α (DGL-α). To our surprise, this form of synaptic plasticity was completely missing in FMRP-KO mice. Neither basal eCB levels nor CB1 receptor function was changed, but a significant decrease in mGlu5-induced DGL-α activity was observed in FMRP-KO mice suggesting that FMRP loss resulted in a functional uncoupling of mGlu5 …