Neuronal Adenosine A2A Receptors Are Critical Mediators of Neurodegeneration Triggered by Convulsions
Autor(a) principal: | |
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Data de Publicação: | 2018 |
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/10316/107549 https://doi.org/10.1523/ENEURO.0385-18.2018 |
Resumo: | Neurodegeneration is a process transversal to neuropsychiatric diseases and the understanding of its mechanisms should allow devising strategies to prevent this irreversible step in brain diseases. Neurodegeneration caused by seizures is a critical step in the aggravation of temporal lobe epilepsy, but its mechanisms remain undetermined. Convulsions trigger an elevation of extracellular adenosine and upregulate adenosine A2A receptors (A2AR), which have been associated with the control of neurodegenerative diseases. Using the rat and mouse kainate model of temporal lobe epilepsy, we now tested whether A2AR control convulsions-induced hippocampal neurodegeneration. The pharmacological or genetic blockade of A2AR did not affect kainate-induced convulsions but dampened the subsequent neurotoxicity. This neurotoxicity began with a rapid A2AR upregulation within glutamatergic synapses (within 2 h), through local translation of synaptic A2AR mRNA. This bolstered A2AR-mediated facilitation of glutamate release and of long-term potentiation (LTP) in CA1 synapses (4 h), triggered a subsequent synaptotoxicity, heralded by decreased synaptic plasticity and loss of synaptic markers coupled to calpain activation (12 h), that predated overt neuronal loss (24 h). All modifications were prevented by the deletion of A2AR selectively in forebrain neurons. This shows that synaptic A2AR critically control synaptic excitotoxicity, which underlies the development of convulsions-induced neurodegeneration. |
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Neuronal Adenosine A2A Receptors Are Critical Mediators of Neurodegeneration Triggered by Convulsionsadenosineconvulsionsneuroprotectionsynapsesynaptotoxicitysynatic plasticityAdenosine A2 Receptor AntagonistsAmygdalaAnimalsCells, CulturedConvulsantsEpilepsyHippocampusKainic AcidKindling, NeurologicMaleMiceMice, Inbred C57BLMice, KnockoutNerve DegenerationNeuronsProtein BindingPyrimidinesRatsRats, WistarReceptor, Adenosine A2ASynaptic TransmissionTriazolesNeurodegeneration is a process transversal to neuropsychiatric diseases and the understanding of its mechanisms should allow devising strategies to prevent this irreversible step in brain diseases. Neurodegeneration caused by seizures is a critical step in the aggravation of temporal lobe epilepsy, but its mechanisms remain undetermined. Convulsions trigger an elevation of extracellular adenosine and upregulate adenosine A2A receptors (A2AR), which have been associated with the control of neurodegenerative diseases. Using the rat and mouse kainate model of temporal lobe epilepsy, we now tested whether A2AR control convulsions-induced hippocampal neurodegeneration. The pharmacological or genetic blockade of A2AR did not affect kainate-induced convulsions but dampened the subsequent neurotoxicity. This neurotoxicity began with a rapid A2AR upregulation within glutamatergic synapses (within 2 h), through local translation of synaptic A2AR mRNA. This bolstered A2AR-mediated facilitation of glutamate release and of long-term potentiation (LTP) in CA1 synapses (4 h), triggered a subsequent synaptotoxicity, heralded by decreased synaptic plasticity and loss of synaptic markers coupled to calpain activation (12 h), that predated overt neuronal loss (24 h). All modifications were prevented by the deletion of A2AR selectively in forebrain neurons. This shows that synaptic A2AR critically control synaptic excitotoxicity, which underlies the development of convulsions-induced neurodegeneration.Society for Neuroscience2018info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/107549http://hdl.handle.net/10316/107549https://doi.org/10.1523/ENEURO.0385-18.2018eng2373-2822Canas, Paula M.Porciúncula, Lisiane O.Simões, Ana PatríciaAugusto, Elisabete de OliveiraSilva, Henrique B.Machado, Nuno J.Gonçalves, NélioAlfaro, Tiago M.Gonçalves, Francisco Q.Araújo, Inês M.Real, Joana I.Coelho, Joana E.Andrade, Geanne M.Almeida, Ramiro D.Chen, Jiang-FanKöfalvi, AttilaAgostinho, PaulaCunha, 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:RCAAP2023-07-19T11:22:54Zoai:estudogeral.uc.pt:10316/107549Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:23:53.669413Repositório 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 |
Neuronal Adenosine A2A Receptors Are Critical Mediators of Neurodegeneration Triggered by Convulsions |
title |
Neuronal Adenosine A2A Receptors Are Critical Mediators of Neurodegeneration Triggered by Convulsions |
spellingShingle |
Neuronal Adenosine A2A Receptors Are Critical Mediators of Neurodegeneration Triggered by Convulsions Canas, Paula M. adenosine convulsions neuroprotection synapse synaptotoxicity synatic plasticity Adenosine A2 Receptor Antagonists Amygdala Animals Cells, Cultured Convulsants Epilepsy Hippocampus Kainic Acid Kindling, Neurologic Male Mice Mice, Inbred C57BL Mice, Knockout Nerve Degeneration Neurons Protein Binding Pyrimidines Rats Rats, Wistar Receptor, Adenosine A2A Synaptic Transmission Triazoles |
title_short |
Neuronal Adenosine A2A Receptors Are Critical Mediators of Neurodegeneration Triggered by Convulsions |
title_full |
Neuronal Adenosine A2A Receptors Are Critical Mediators of Neurodegeneration Triggered by Convulsions |
title_fullStr |
Neuronal Adenosine A2A Receptors Are Critical Mediators of Neurodegeneration Triggered by Convulsions |
title_full_unstemmed |
Neuronal Adenosine A2A Receptors Are Critical Mediators of Neurodegeneration Triggered by Convulsions |
title_sort |
Neuronal Adenosine A2A Receptors Are Critical Mediators of Neurodegeneration Triggered by Convulsions |
author |
Canas, Paula M. |
author_facet |
Canas, Paula M. Porciúncula, Lisiane O. Simões, Ana Patrícia Augusto, Elisabete de Oliveira Silva, Henrique B. Machado, Nuno J. Gonçalves, Nélio Alfaro, Tiago M. Gonçalves, Francisco Q. Araújo, Inês M. Real, Joana I. Coelho, Joana E. Andrade, Geanne M. Almeida, Ramiro D. Chen, Jiang-Fan Köfalvi, Attila Agostinho, Paula Cunha, Rodrigo A. |
author_role |
author |
author2 |
Porciúncula, Lisiane O. Simões, Ana Patrícia Augusto, Elisabete de Oliveira Silva, Henrique B. Machado, Nuno J. Gonçalves, Nélio Alfaro, Tiago M. Gonçalves, Francisco Q. Araújo, Inês M. Real, Joana I. Coelho, Joana E. Andrade, Geanne M. Almeida, Ramiro D. Chen, Jiang-Fan Köfalvi, Attila Agostinho, Paula Cunha, Rodrigo A. |
author2_role |
author author author author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Canas, Paula M. Porciúncula, Lisiane O. Simões, Ana Patrícia Augusto, Elisabete de Oliveira Silva, Henrique B. Machado, Nuno J. Gonçalves, Nélio Alfaro, Tiago M. Gonçalves, Francisco Q. Araújo, Inês M. Real, Joana I. Coelho, Joana E. Andrade, Geanne M. Almeida, Ramiro D. Chen, Jiang-Fan Köfalvi, Attila Agostinho, Paula Cunha, Rodrigo A. |
dc.subject.por.fl_str_mv |
adenosine convulsions neuroprotection synapse synaptotoxicity synatic plasticity Adenosine A2 Receptor Antagonists Amygdala Animals Cells, Cultured Convulsants Epilepsy Hippocampus Kainic Acid Kindling, Neurologic Male Mice Mice, Inbred C57BL Mice, Knockout Nerve Degeneration Neurons Protein Binding Pyrimidines Rats Rats, Wistar Receptor, Adenosine A2A Synaptic Transmission Triazoles |
topic |
adenosine convulsions neuroprotection synapse synaptotoxicity synatic plasticity Adenosine A2 Receptor Antagonists Amygdala Animals Cells, Cultured Convulsants Epilepsy Hippocampus Kainic Acid Kindling, Neurologic Male Mice Mice, Inbred C57BL Mice, Knockout Nerve Degeneration Neurons Protein Binding Pyrimidines Rats Rats, Wistar Receptor, Adenosine A2A Synaptic Transmission Triazoles |
description |
Neurodegeneration is a process transversal to neuropsychiatric diseases and the understanding of its mechanisms should allow devising strategies to prevent this irreversible step in brain diseases. Neurodegeneration caused by seizures is a critical step in the aggravation of temporal lobe epilepsy, but its mechanisms remain undetermined. Convulsions trigger an elevation of extracellular adenosine and upregulate adenosine A2A receptors (A2AR), which have been associated with the control of neurodegenerative diseases. Using the rat and mouse kainate model of temporal lobe epilepsy, we now tested whether A2AR control convulsions-induced hippocampal neurodegeneration. The pharmacological or genetic blockade of A2AR did not affect kainate-induced convulsions but dampened the subsequent neurotoxicity. This neurotoxicity began with a rapid A2AR upregulation within glutamatergic synapses (within 2 h), through local translation of synaptic A2AR mRNA. This bolstered A2AR-mediated facilitation of glutamate release and of long-term potentiation (LTP) in CA1 synapses (4 h), triggered a subsequent synaptotoxicity, heralded by decreased synaptic plasticity and loss of synaptic markers coupled to calpain activation (12 h), that predated overt neuronal loss (24 h). All modifications were prevented by the deletion of A2AR selectively in forebrain neurons. This shows that synaptic A2AR critically control synaptic excitotoxicity, which underlies the development of convulsions-induced neurodegeneration. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018 |
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/10316/107549 http://hdl.handle.net/10316/107549 https://doi.org/10.1523/ENEURO.0385-18.2018 |
url |
http://hdl.handle.net/10316/107549 https://doi.org/10.1523/ENEURO.0385-18.2018 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
2373-2822 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Society for Neuroscience |
publisher.none.fl_str_mv |
Society for Neuroscience |
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 |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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