Author(s): Tanqueiro, Sara ; Mouro, Francisco ; Ferreira, Catarina B. ; Freitas, Céline ; Fonseca-Gomes, João ; Simões Do Couto, Frederico ; Sebastião, Ana M ; Dawson, Neil ; Diógenes, Maria José
Date: 2021
Persistent ID: http://hdl.handle.net/10451/48122
Origin: Repositório da Universidade de Lisboa
Project/scholarship: info:eu-repo/grantAgreement/EC/H2020/692340/EU; info:eu-repo/grantAgreement/EC/H2020/952455/EU;
Subject(s): BDNF; PFC; TrkB-FL; Cognitive deficits; Phencyclidine
Copyright © 2021, © SAGE Publications
Background: 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.
The 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.
