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Title: Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction
Authors: Augusto, Elisabete de Oliveira 
Gonçalves, Francisco Q.
Real, Joana E. 
Silva, Henrique B.
Pochmann, Daniela 
Silva, Tiago S.
Matos, Marco
Gonçalves, Nélio da Mota 
Tomé, Ângelo R. 
Chen, Jiang-Fan 
Canas, Paula M.
Cunha, Rodrigo A. 
Keywords: A(2A) receptors; ATP; Astrocytes; CD73; Ecto-nucleotidases; Epilepsy; Memory; P2 receptors
Issue Date: Sep-2021
Publisher: Elsevier
Project: BrainHealth 2020 - Detecção Precoce, Neuro-modulação e Terapias Avançadas para Neuropatologias 
POCI-01-0145-FEDER- 03127 
Serial title, monograph or event: Neurobiology of Disease
Volume: 157
Abstract: Extracellular ATP is a danger signal to the brain and contributes to neurodegeneration in animal models of Alzheimer's disease through its extracellular catabolism by CD73 to generate adenosine, bolstering the activation of adenosine A2A receptors (A2AR). Convulsive activity leads to increased ATP release, with the resulting morphological alterations being eliminated by A2AR blockade. However, it is not known if upon convulsions there is a CD73-mediated coupling between ATP release and A2AR overactivation, causing neurodegeneration. We now show that kainate-induced convulsions trigger a parallel increase of ATP release and of CD73 and A2AR densities in synapses and astrocytes of the mouse hippocampus. Notably, the genetic deletion of CD73 attenuates neuronal degeneration but has no impact on astrocytic modifications in the hippocampus upon kainate-induced convulsions. Furthermore, kainate-induced convulsions cause a parallel deterioration of hippocampal long-term potentiation (LTP) and hippocampal-dependent memory performance, which is eliminated by knocking out CD73. This demonstrates the key role of the ATP release/CD73/A2AR pathway to selectively control synaptic dysfunction and neurodegeneration following an acute brain insult, paving the way to consider CD73 as a new therapeutic target to prevent neuronal damage upon acute brain damage.
ISSN: 09699961
DOI: 10.1016/j.nbd.2021.105441
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
FMUC Medicina - Artigos em Revistas Internacionais
FCTUC Ciências da Vida - Artigos em Revistas Internacionais

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