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

Tanqueiro, Sara R and Mouro, Francisco M and Ferreira, Catarina B and Freitas, Céline F and Fonseca-Gomes, João and Simões do Couto, Frederico and Sebastião, Ana M and Dawson, Neil and Diógenes, Maria J (2021) 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. Journal of Psychopharmacology. ISSN 0269-8811

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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.

Item Type:
Journal Article
Journal or Publication Title:
Journal of Psychopharmacology
Additional Information:
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/
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2700/2736
Subjects:
ID Code:
155948
Deposited By:
Deposited On:
09 Jun 2021 12:10
Refereed?:
Yes
Published?:
Published
Last Modified:
13 Jun 2021 05:48