Impairment of adenosinergic system in Rett syndrome: novel therapeutic target to boost BDNF signalling
| Autor(a) principal: | |
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| Data de Publicação: | 2020 |
| 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/10451/49719 |
Resumo: | © 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/) |
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Impairment of adenosinergic system in Rett syndrome: novel therapeutic target to boost BDNF signallingAdenosinergic systemBrain-derived neurotrophic factor (BDNF)Mecp2 knockout modelRett syndromeTrkB receptors© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/)Rett syndrome (RTT; OMIM#312750) is mainly caused by mutations in the X-linked MECP2 gene (methyl-CpG-binding protein 2 gene; OMIM*300005), which leads to impairments in the brain-derived neurotrophic factor (BDNF) signalling. The boost of BDNF mediated effects would be a significant breakthrough but it has been hampered by the difficulty to administer BDNF to the central nervous system. Adenosine, an endogenous neuromodulator, may accomplish that role since through A2AR it potentiates BDNF synaptic actions in healthy animals. We thus characterized several hallmarks of the adenosinergic and BDNF signalling in RTT and explored whether A2AR activation could boost BDNF actions. For this study, the RTT animal model, the Mecp2 knockout (Mecp2-/y) (B6.129P2 (C)-Mecp2tm1.1Bird/J) mouse was used. Whenever possible, parallel data was also obtained from post-mortem brain samples from one RTT patient. Ex vivo extracellular recordings of field excitatory post-synaptic potentials in CA1 hippocampal area were performed to evaluate synaptic transmission and long-term potentiation (LTP). RT-PCR was used to assess mRNA levels and Western Blot or radioligand binding assays were performed to evaluate protein levels. Changes in cortical and hippocampal adenosine content were assessed by liquid chromatography with diode array detection (LC/DAD). Hippocampal ex vivo experiments revealed that the facilitatory actions of BDNF upon LTP is absent in Mecp2-/y mice and that TrkB full-length (TrkB-FL) receptor levels are significantly decreased. Extracts of the hippocampus and cortex of Mecp2-/y mice revealed less adenosine amount as well as less A2AR protein levels when compared to WT littermates, which may partially explain the deficits in adenosinergic tonus in these animals. Remarkably, the lack of BDNF effect on hippocampal LTP in Mecp2-/y mice was overcome by selective activation of A2AR with CGS21680. Overall, in Mecp2-/y mice there is an impairment on adenosinergic system and BDNF signalling. These findings set the stage for adenosine-based pharmacological therapeutic strategies for RTT, highlighting A2AR as a therapeutic target in this devastating pathology.The work was supported by a joint research grant awarded to TMR from Fundação Calouste Gulbenkian and FMUL (20130002/PEC/BG); Fundação para a Ciência e Tecnologia (FCT, AdoRett – LISBOA-01-0145-FEDER-031929/2017 and FCT SFRH/BD/118238/2016 granted to CML); Universidade de Lisboa (grant awarded by CML BD2015); the Association Française du Syndrome de Rett; Program “Educação pela Ciência” Bolsas CHLN/FMUL – GAPIC (Project No. 20190017); Twinning action (SynaNet) from the EU H2020 Programme; and the UID/BIM/50005/2019, project financed by the FCT/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES), through the Fundos do Orçamento de Estado. The work performed at ICBAS/MedInUP by PCS and TMC was partially supported by FCT (FEDER funding, project UID/BIM/4308/2019 and UIDP/04308/2020).ElsevierRepositório da Universidade de LisboaMiranda-Lourenço, CatarinaDuarte, Sofia T.Palminha, CátiaGaspar, CláudiaRodrigues, Tiago M.Magalhães-Cardoso, TeresaRei, NádiaColino-Oliveira, MarianaGomes, RuiFerreira, SaraRosa, JéssicaXapelli, SaraArmstrong, JudithGarcía-Cazorla, ÀngelsCorreia-de-Sá, PauloSebastião, Ana MDiógenes, Maria José2021-09-30T11:40:50Z20202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/49719engNeurobiol Dis. 2020 Nov;145:105043.0969-996110.1016/j.nbd.2020.1050431095-953Xinfo: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:RCAAP2023-11-08T16:53:40Zoai:repositorio.ul.pt:10451/49719Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:01:19.700053Repositório 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 |
Impairment of adenosinergic system in Rett syndrome: novel therapeutic target to boost BDNF signalling |
| title |
Impairment of adenosinergic system in Rett syndrome: novel therapeutic target to boost BDNF signalling |
| spellingShingle |
Impairment of adenosinergic system in Rett syndrome: novel therapeutic target to boost BDNF signalling Miranda-Lourenço, Catarina Adenosinergic system Brain-derived neurotrophic factor (BDNF) Mecp2 knockout model Rett syndrome TrkB receptors |
| title_short |
Impairment of adenosinergic system in Rett syndrome: novel therapeutic target to boost BDNF signalling |
| title_full |
Impairment of adenosinergic system in Rett syndrome: novel therapeutic target to boost BDNF signalling |
| title_fullStr |
Impairment of adenosinergic system in Rett syndrome: novel therapeutic target to boost BDNF signalling |
| title_full_unstemmed |
Impairment of adenosinergic system in Rett syndrome: novel therapeutic target to boost BDNF signalling |
| title_sort |
Impairment of adenosinergic system in Rett syndrome: novel therapeutic target to boost BDNF signalling |
| author |
Miranda-Lourenço, Catarina |
| author_facet |
Miranda-Lourenço, Catarina Duarte, Sofia T. Palminha, Cátia Gaspar, Cláudia Rodrigues, Tiago M. Magalhães-Cardoso, Teresa Rei, Nádia Colino-Oliveira, Mariana Gomes, Rui Ferreira, Sara Rosa, Jéssica Xapelli, Sara Armstrong, Judith García-Cazorla, Àngels Correia-de-Sá, Paulo Sebastião, Ana M Diógenes, Maria José |
| author_role |
author |
| author2 |
Duarte, Sofia T. Palminha, Cátia Gaspar, Cláudia Rodrigues, Tiago M. Magalhães-Cardoso, Teresa Rei, Nádia Colino-Oliveira, Mariana Gomes, Rui Ferreira, Sara Rosa, Jéssica Xapelli, Sara Armstrong, Judith García-Cazorla, Àngels Correia-de-Sá, Paulo Sebastião, Ana M Diógenes, Maria José |
| author2_role |
author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
| dc.contributor.author.fl_str_mv |
Miranda-Lourenço, Catarina Duarte, Sofia T. Palminha, Cátia Gaspar, Cláudia Rodrigues, Tiago M. Magalhães-Cardoso, Teresa Rei, Nádia Colino-Oliveira, Mariana Gomes, Rui Ferreira, Sara Rosa, Jéssica Xapelli, Sara Armstrong, Judith García-Cazorla, Àngels Correia-de-Sá, Paulo Sebastião, Ana M Diógenes, Maria José |
| dc.subject.por.fl_str_mv |
Adenosinergic system Brain-derived neurotrophic factor (BDNF) Mecp2 knockout model Rett syndrome TrkB receptors |
| topic |
Adenosinergic system Brain-derived neurotrophic factor (BDNF) Mecp2 knockout model Rett syndrome TrkB receptors |
| description |
© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/) |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 2020-01-01T00:00:00Z 2021-09-30T11:40:50Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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http://hdl.handle.net/10451/49719 |
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http://hdl.handle.net/10451/49719 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
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Neurobiol Dis. 2020 Nov;145:105043. 0969-9961 10.1016/j.nbd.2020.105043 1095-953X |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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Elsevier |
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Elsevier |
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