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  • Tanqueiro et al. 2021

    Rights statement: The final, definitive version of this article has been published in the Journal, Journal of Psychopharmacology, ? (?), 2021, © SAGE Publications Ltd, 2021 by SAGE Publications Ltd at the Journal of Psychopharmacology page: https://journals.sagepub.com/home/jop on SAGE Journals Online: http://journals.sagepub.com/

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    Available under license: CC BY-NC: Creative Commons Attribution-NonCommercial 4.0 International License

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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

Research output: Contribution to journalJournal articlepeer-review

E-pub ahead of print
  • Sara R Tanqueiro
  • Francisco M Mouro
  • Catarina B Ferreira
  • Céline F Freitas
  • João Fonseca-Gomes
  • Frederico Simões do Couto
  • Ana M Sebastião
  • Neil Dawson
  • Maria J Diógenes
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<mark>Journal publication date</mark>19/05/2021
<mark>Journal</mark>Journal of Psychopharmacology
Publication StatusE-pub ahead of print
Early online date19/05/21
<mark>Original language</mark>English

Abstract

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.

Bibliographic note

The final, definitive version of this article has been published in the Journal, Journal of Psychopharmacology, ? (?), 2021, © SAGE Publications Ltd, 2021 by SAGE Publications Ltd at the Journal of Psychopharmacology page: https://journals.sagepub.com/home/jop on SAGE Journals Online: http://journals.sagepub.com/