Ecto-5′-Nucleotidase (CD73)-Mediated Formation of Adenosine Is Critical for the Striatal Adenosine A2A Receptor Functions

Adenosine is a neuromodulator acting through inhibitory A(1) receptors (A(1)Rs) and facilitatory A(2A)Rs, which have similar affinities for adenosine. It has been shown that the activity of intracellular adenosine kinase preferentially controls the activation of A(1)Rs, but the source of the adenosine activating A(2A)Rs is unknown. We now show that ecto-5'-nucleotidase (CD73), the major enzyme able to convert extracellular AMP into adenosine, colocalizes with A(2A)Rs in the basal ganglia. In addition to astrocytes, striatal CD73 is prominently localized to postsynaptic sites. Notably, CD73 coimmunoprecipitated with A(2A)Rs and proximity ligation assays confirmed the close proximity of CD73 and A(2A)Rs in the striatum. Accordingly, the cAMP formation in synaptosomes as well as the hypolocomotion induced by a novel A(2A)R prodrug that requires CD73 metabolization to activate A(2A)Rs were observed in wild-type mice, but not in CD73 knock-out (KO) mice or A(2A)R KO mice. Moreover, CD73 KO mice displayed increased working memory performance and a blunted amphetamine-induced sensitization, mimicking the phenotype of global or forebrain-A(2A)R KO mice, as well as upon pharmacological A(2A)R blockade. These results show that CD73-mediated formation of extracellular adenosine is responsible for the activation of striatal A(2A)R function. This study points to CD73 as a new target that can fine-tune A(2A)R activity, and a novel therapeutic target to manipulate A(2A)R-mediated control of striatal function and neurodegeneration.