Adenosine A_2A receptor inhibition reduces synaptic and cognitive hippocampal alterations in Fmr1 KO mice.

ABSTRACT: 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_2ARs), 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_2ARs 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_2AR antagonist ZM241385 and strongly potentiated by the A_2AR agonist CGS21680, suggesting that the functional synergistic coupling between the two receptors could be increased in FXS. To verify if chronic A_2AR blockade could reverse the FXS phenotypes, we treated the Fmr1 KO mice with istradefylline, an A_2AR 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_2AR mRNA as a target of FMRP. Our results show that the pharmacological blockade of A_2ARs partially restores some of the phenotypes of Fmr1 KO mice, both by reducing mGlu5R functioning and by acting on other A_2AR-related downstream targets.

SUBMITTER: Ferrante A 

PROVIDER: S-EPMC7864914 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature