Restricted accessResearch articleFirst published online 2021-6
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
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.
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