CD73-Mediated Formation of Extracellular Adenosine Is Responsible for Adenosine A 2A Receptor-Mediated Control of Fear Memory and Amygdala Plasticity.

Adenosine A 2A receptors (A 2A R) control fear memory and the underlying processes of synaptic plasticity in the amygdala. In other brain regions, A 2A R activation is ensured by ATP-derived extracellular adenosine formed by ecto-5'-nucleotidase or CD73. We now tested whether CD73 is also responsible to provide for the activation of A 2A R in controlling fear memory and amygdala long-term potentiation (LTP). The bilateral intracerebroventricular injection of the CD73 inhibitor αβ-methylene ADP (AOPCP, 1 nmol/ventricle/day) phenocopied the effect of the A 2A R blockade by decreasing the expression of fear memory, an effect disappearing in CD73-knockout (KO) mice and in forebrain neuronal A 2A R-KO mice. In the presence of PPADS (20 μM) to eliminate any modification of ATP/ADP-mediated P2 receptor effects, both AOPCP (100 μM) and the A 2A R antagonist, SCH58261 (50 nM), decreased LTP magnitude in synapses of projection from the external capsula into the lateral amygdala, an effect eliminated in slices from both forebrain neuronal A 2A R-KO mice and CD73-KO mice. These data indicate a key role of CD73 in the process of A 2A R-mediated control of fear memory and underlying synaptic plasticity processes in the amygdala, paving the way to envisage CD73 as a new therapeutic target to interfere with abnormal fear-like emotional processing.