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Sustained NMDA receptor hypofunction impairs brain-derived neurotropic factor signalling in the PFC, but not in the hippocampus, and disturbs PFC-dependent cognition in mice

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dc.contributor.authorTanqueiro, Sara
dc.contributor.authorMouro, Francisco
dc.contributor.authorFerreira, Catarina B.
dc.contributor.authorFreitas, Céline
dc.contributor.authorFonseca-Gomes, João
dc.contributor.authorSimões Do Couto, Frederico
dc.contributor.authorSebastião, Ana M
dc.contributor.authorDawson, Neil
dc.contributor.authorDiógenes, Maria José
dc.date.accessioned2021-05-24T16:37:12Z
dc.date.available2021-05-24T16:37:12Z
dc.date.issued2021
dc.descriptionCopyright © 2021, © SAGE Publicationspt_PT
dc.description.abstractBackground: Cognitive deficits profoundly impact on the quality of life of patients with schizophrenia. Alterations in brain derived neurotrophic factor (BDNF) signalling, which regulates synaptic function through the activation of full-length tropomyosin-related kinase B receptors (TrkB-FL), are implicated in the aetiology of schizophrenia, as is N-methyl-D-aspartate receptor (NMDA-R) hypofunction. However, whether NMDA-R hypofunction contributes to the disrupted BDNF signalling seen in patients remains unknown. Aims: The purpose of this study was to characterise BDNF signalling and function in a preclinical rodent model relevant to schizophrenia induced by prolonged NMDA-R hypofunction. Methods: Using the subchronic phencyclidine (PCP) model, we performed electrophysiology approaches, molecular characterisation and behavioural analysis. Results: The data showed that prolonged NMDA-R antagonism, induced by subchronic PCP treatment, impairs long-term potentiation (LTP) and the facilitatory effect of BDNF upon LTP in the medial prefrontal cortex (PFC) of adult mice. Additionally, TrkB-FL receptor expression is decreased in the PFC of these animals. By contrast, these changes were not present in the hippocampus of PCP-treated mice. Moreover, BDNF levels were not altered in the hippocampus or PFC of PCP-treated mice. Interestingly, these observations are paralleled by impaired performance in PFC-dependent cognitive tests in mice treated with PCP. Conclusions: Overall, these data suggest that NMDA-R hypofunction induces dysfunctional BDNF signalling in the PFC, but not in the hippocampus, which may contribute to the PFC-dependent cognitive deficits seen in the subchronic PCP model. Additionally, these data suggest that targeting BDNF signalling may be a mechanism to improve PFC-dependent cognitive dysfunction in schizophrenia.pt_PT
dc.description.sponsorshipThe author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by LISBOA-01-0145-FEDER-007391, project co-funded by FEDER through POR Lisboa 2020 (Programa Operacional Regional de Lisboa) from PORTUGAL 2020 and Fundação para a Ciência e Tecnologia (FCT), by European Union’s Horizon 2020 research and innovation programme under grant agreement No 692340 (SynaNet) and No 952455 (EpiEpinet) and GAPIC (20180014). SRT was in receipt of SFRH/BD/128091/2016 FCT fellowship.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationJ Psychopharmacol. 2021 May 19:2698811211008560pt_PT
dc.identifier.doi10.1177/02698811211008560pt_PT
dc.identifier.eissn1461-7285
dc.identifier.issn0269-8811
dc.identifier.urihttp://hdl.handle.net/10451/48122
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSAGE Publishingpt_PT
dc.relationLISBOA-01-0145-FEDER-007391pt_PT
dc.relationNeurologic and Psychiatric Disorders: from synapses to networks
dc.relationEpileptogenesis and Epilepsy Network: from genes, synapses and circuits to pave the way for novel drugs and strategies
dc.relationSFRH/BD/128091/2016pt_PT
dc.relation.publisherversionhttps://journals.sagepub.com/home/joppt_PT
dc.subjectFator neurotrófico derivado do cérebro (BDNF)pt_PT
dc.subjectPFCpt_PT
dc.subjectTrkB-FLpt_PT
dc.subjectCognitive deficitspt_PT
dc.subjectPhencyclidinept_PT
dc.titleSustained NMDA receptor hypofunction impairs brain-derived neurotropic factor signalling in the PFC, but not in the hippocampus, and disturbs PFC-dependent cognition in micept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleNeurologic and Psychiatric Disorders: from synapses to networks
oaire.awardTitleEpileptogenesis and Epilepsy Network: from genes, synapses and circuits to pave the way for novel drugs and strategies
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/692340/EU
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/952455/EU
oaire.citation.titleJournal of Psychopharmacologypt_PT
oaire.fundingStreamH2020
oaire.fundingStreamH2020
person.familyNameTanqueiro
person.familyNameMouro
person.familyNameFreitas
person.familyNameFonseca-Gomes
person.familyNameSimões do Couto
person.familyNameSebastião
person.familyNamede Oliveira Diógenes Nogueira
person.givenNameSara
person.givenNameFrancisco
person.givenNameCéline
person.givenNameJoão
person.givenNameFrederico
person.givenNameAna M
person.givenNameMaria José
person.identifier548147
person.identifier.ciencia-id6818-4322-9ED9
person.identifier.ciencia-idA217-D5D0-E9BF
person.identifier.ciencia-idD117-0296-8086
person.identifier.ciencia-idF112-55E8-E37E
person.identifier.ciencia-id4B10-886B-DAFC
person.identifier.orcid0000-0002-9151-7149
person.identifier.orcid0000-0002-7141-8418
person.identifier.orcid0000-0002-2396-6516
person.identifier.orcid0000-0001-7915-3517
person.identifier.orcid0000-0002-3916-2598
person.identifier.orcid0000-0001-9030-6115
person.identifier.orcid0000-0001-5486-6246
person.identifier.ridJ-9374-2017
person.identifier.scopus-author-id14621494400
person.identifier.scopus-author-id7004409879
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
project.funder.nameEuropean Commission
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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