Neuronal Adenosine A2A Receptors Are Critical Mediators of Neurodegeneration Triggered by Convulsions

Detalhes bibliográficos
Autor(a) principal: Canas, Paula M.
Data de Publicação: 2018
Outros Autores: 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.
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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spelling 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
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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)
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