Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/95729 https://doi.org/10.1016/j.nbd.2021.105441 |
Resumo: | 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. |
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Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunctionA(2A) receptors; ATP; Astrocytes; CD73; Ecto-nucleotidases; Epilepsy; Memory; P2 receptorsExtracellular 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.Supported by La Caixa Foundation (LCF/PR/HP17/52190001).Elsevier2021-09info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/95729http://hdl.handle.net/10316/95729https://doi.org/10.1016/j.nbd.2021.105441eng09699961Augusto, Elisabete de OliveiraGonçalves, Francisco Q.Real, Joana E.Silva, Henrique B.Pochmann, DanielaSilva, Tiago S.Matos, MarcoGonçalves, Nélio da MotaTomé, Ângelo R.Chen, Jiang-FanCanas, Paula M.Cunha, Rodrigo A.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2022-12-12T11:48:06Zoai:estudogeral.uc.pt:10316/95729Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:14:09.002872Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction |
title |
Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction |
spellingShingle |
Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction Augusto, Elisabete de Oliveira A(2A) receptors; ATP; Astrocytes; CD73; Ecto-nucleotidases; Epilepsy; Memory; P2 receptors |
title_short |
Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction |
title_full |
Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction |
title_fullStr |
Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction |
title_full_unstemmed |
Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction |
title_sort |
Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction |
author |
Augusto, Elisabete de Oliveira |
author_facet |
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. |
author_role |
author |
author2 |
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. |
author2_role |
author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
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. |
dc.subject.por.fl_str_mv |
A(2A) receptors; ATP; Astrocytes; CD73; Ecto-nucleotidases; Epilepsy; Memory; P2 receptors |
topic |
A(2A) receptors; ATP; Astrocytes; CD73; Ecto-nucleotidases; Epilepsy; Memory; P2 receptors |
description |
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. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-09 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/95729 http://hdl.handle.net/10316/95729 https://doi.org/10.1016/j.nbd.2021.105441 |
url |
http://hdl.handle.net/10316/95729 https://doi.org/10.1016/j.nbd.2021.105441 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
09699961 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Elsevier |
publisher.none.fl_str_mv |
Elsevier |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
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1799134038633480192 |