Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction
Neurobiology of Disease. 2021-09-01; 157: 105441
DOI: 10.1016/j.nbd.2021.105441
Lire sur PubMed
Augusto E(1), Gonçalves FQ(2), Real JE(2), Silva HB(2), Pochmann D(2), Silva
TS(2), Matos M(1), Gonçalves N(2), Tomé ÂR(3), Chen JF(4), Canas PM(2), Cunha
RA(5).
Author information:
(1)CNC-Center for Neuroscience and Cell Biology, University of Coimbra,
Portugal; Department of Neurology, Boston University School of Medicine, Boston,
MA 02118, USA.
(2)CNC-Center for Neuroscience and Cell Biology, University of Coimbra,
Portugal.
(3)CNC-Center for Neuroscience and Cell Biology, University of Coimbra,
Portugal; Department of Life Sciences, Faculty of Sciences and Technology,
University of Coimbra, Portugal.
(4)Department of Neurology, Boston University School of Medicine, Boston, MA
02118, USA; Molecular Neuropharmacology Lab, School of Optometry and
Ophthalmology, Wenzhou Medical University, Wenzhou, China.
(5)CNC-Center for Neuroscience and Cell Biology, University of Coimbra,
Portugal; Faculty of Medicine, University of Coimbra, Portugal. Electronic
address: .
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.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.