Fig. 2

ECS dysfunction in FXS due to lack of FMRP. Lack of FMRP in FXS leads to (1) reduced expression of DGKκ and abnormal trafficking of DAGL mRNA, which results in (2) ectopic/abnormal production of 2-AG and release into the synaptic cleft, which causes (3) β-arrestin recruitment, internalization, and desensitization of CB₁ receptors, resulting in (4) loss of the normal retrograde inhibitory signaling and (5) increased glutamate release and activation of mGluR5 receptors and (6) altered GABA release. 2-AG, 2-arachidonoylglycerol; β-arr, β-arrestin; CB1, cannabinoid type 1 receptor; CNS, central nervous system; DAG, diacylglycerol; DAGL, diacylglycerol lipase; DGKκ, diacylglycerol kinase-κ; ECS, endocannabinoid system; FMRP, FMR1 protein; FXS, fragile X syndrome; G, G proteins; GABA, γ-aminobutyric acid; mGluR5, group I metabotropic glutamate receptor 5; mRNA, messenger RNA; PA, phosphatidic acid; PIP2, phosphatidylinositol-4,5-bisphosphate; PLC, phospholipase C