Rights statement: The final, definitive version of this article has been published in the Journal, Journal of Psychopharmacology, 35 (6), 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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Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - 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
AU - Tanqueiro, Sara R
AU - Mouro, Francisco M
AU - Ferreira, Catarina B
AU - Freitas, Céline F
AU - Fonseca-Gomes, João
AU - Simões do Couto, Frederico
AU - Sebastião, Ana M
AU - Dawson, Neil
AU - Diógenes, Maria J
N1 - The final, definitive version of this article has been published in the Journal, Journal of Psychopharmacology, 35 (6), 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/
PY - 2021/6/1
Y1 - 2021/6/1
N2 - 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.
AB - 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.
KW - BDNF
KW - cognitive deficits
KW - PFC
KW - phencyclidine
KW - TrkB-FL
U2 - 10.1177/02698811211008560
DO - 10.1177/02698811211008560
M3 - Journal article
C2 - 34008450
VL - 35
SP - 730
EP - 743
JO - Journal of Psychopharmacology
JF - Journal of Psychopharmacology
SN - 0269-8811
IS - 6
ER -