In fragile X syndrome (FXS) the lack of the fragile X mental retardation protein (FMRP) leads to exacerbated signaling through the metabotropic glutamate receptors 5 (mGlu5Rs). The adenosine A _2A receptors (A _2A Rs), modulators of neuronal damage, could play a role in FXS. A synaptic colocalization and a strong permissive interaction between A _2A and mGlu5 receptors in the hippocampus have been previously reported, suggesting that blocking A _2A Rs might normalize the mGlu5R-mediated effects of FXS. To study the cross-talk between A _2A and mGlu5 receptors in the absence of FMRP, we performed extracellular electrophysiology experiments in hippocampal slices of Fmr1 KO mouse. The depression of field excitatory postsynaptic potential (fEPSPs) slope induced by the mGlu5R agonist CHPG was completely blocked by the A _2A R antagonist ZM241385 and strongly potentiated by the A _2A R agonist CGS21680, suggesting that the functional synergistic coupling between the two receptors could be increased in FXS. To verify if chronic A _2A R blockade could reverse the FXS phenotypes, we treated the Fmr1 KO mice with istradefylline, an A _2A R antagonist. We found that hippocampal DHPG-induced long-term depression (LTD), which is abnormally increased in FXS mice, was restored to the WT level. Furthermore, istradefylline corrected aberrant dendritic spine density, specific behavioral alterations, and overactive mTOR, TrkB, and STEP signaling in Fmr1 KO mice. Finally, we identified A _2A R mRNA as a target of FMRP. Our results show that the pharmacological blockade of A _2A Rs partially restores some of the phenotypes of Fmr1 KO mice, both by reducing mGlu5R functioning and by acting on other A _2A R-related downstream targets.