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Title: Increased Synaptic ATP Release and CD73-Mediated Formation of Extracellular Adenosine in the Control of Behavioral and Electrophysiological Modifications Caused by Chronic Stress
Authors: Dias, Liliana 
Pochmann, Daniela 
Lemos, Cristina 
Silva, Henrique B. 
Real, Joana I. 
Gonçalves, Francisco Q. 
Rial, Daniel 
Gonçalves, Nélio 
Simões, Ana Patrícia 
Ferreira, Samira G. 
Agostinho, Paula M. 
Cunha, Rodrigo A. 
Tomé, Ângelo R. 
Keywords: ATP; adenosine; CD73; ecto-5′-nucleotidase; stress; hippocampus; prefrontal cortex; memory; mood; nerve terminals
Issue Date: 5-Apr-2023
Publisher: American Chemical Society
Project: LCF/ PR/HP17/52190001 
CENTRO-01-0145- FEDER-000008 
CENTRO-01-0246- FEDER-000010 
Serial title, monograph or event: ACS Chemical Neuroscience
Volume: 14
Issue: 7
Abstract: Increased ATP release and its extracellular catabolism through CD73 (ecto-5'-nucleotidase) lead to the overactivation of adenosine A2A receptors (A2AR), which occurs in different brain disorders. A2AR blockade blunts mood and memory dysfunction caused by repeated stress, but it is unknown if increased ATP release coupled to CD73-mediated formation of extracellular adenosine is responsible for A2AR overactivation upon repeated stress. This was now investigated in adult rats subject to repeated stress for 14 consecutive days. Frontocortical and hippocampal synaptosomes from stressed rats displayed an increased release of ATP upon depolarization, coupled to an increased density of vesicular nucleotide transporters and of CD73. The continuous intracerebroventricular delivery of the CD73 inhibitor α,β-methylene ADP (AOPCP, 100 μM) during restraint stress attenuated mood and memory dysfunction. Slice electrophysiological recordings showed that restraint stress decreased long-term potentiation both in prefrontocortical layer II/III-layer V synapses and in hippocampal Schaffer fibers-CA1 pyramid synapses, which was prevented by AOPCP, an effect occluded by adenosine deaminase and by the A2AR antagonist SCH58261. These results indicate that increased synaptic ATP release coupled to CD73-mediated formation of extracellular adenosine contributes to mood and memory dysfunction triggered by repeated restraint stress. This prompts considering interventions decreasing ATP release and CD73 activity as novel strategies to mitigate the burden of repeated stress.
ISSN: 1948-7193
DOI: 10.1021/acschemneuro.2c00810
Rights: openAccess
Appears in Collections:FCTUC Ciências da Vida - Artigos em Revistas Internacionais
FMUC Medicina - Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais

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