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

J Psychopharmacol. 2021 Jun;35(6):730-743. doi: 10.1177/02698811211008560. Epub 2021 May 19.


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.

Keywords: BDNF; PFC; TrkB-FL; cognitive deficits; phencyclidine.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Cognition / physiology
  • Cognition Disorders / physiopathology*
  • Disease Models, Animal
  • Hippocampus / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuropsychological Tests
  • Phencyclidine
  • Prefrontal Cortex / pathology
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Schizophrenia / physiopathology*
  • Signal Transduction / physiology


  • Bdnf protein, mouse
  • Brain-Derived Neurotrophic Factor
  • Receptors, N-Methyl-D-Aspartate
  • Phencyclidine