Detalhes do Documento

Schizophrenia is a neuropsychiatric disorder increasingly viewed as a neurodevelopmental pathology that affects individuals of both sexes. It is characterized by positive and negative symptoms, as well as cognitive dysfunction. However, current therapeutic strategies are mainly focused on antipsychotic drugs (APDs), which have very limited efficacy treating the cognitive impairments. Although the pathological mechanisms leading to schizophrenia remain unclear, N-methyl-D-aspartate receptor (NMDA-R) hypofunction is thought to be involved. Furthermore, deregulation of brain-derived neurotrophic factor (BDNF) signalling pathways has also been implicated. BDNF is a neurotrophin which mediates actions by binding to the full-length tyrosine kinase receptor B (TrkB-FL). Neonatal administration of phencyclidine (PCP) to rodents has been reported to induce lasting cognitive deficits, accounting for the developmental aspect of schizophrenia. Therefore, the present thesis sought to characterize the long-term cognitive effects induced by administration of PCP to neonatal mice and evaluate BDNF-mediated signalling both in the hippocampus and PFC, two highly relevant areas involved in the pathophysiology of this disorder. An additional rationale for this work, since schizophrenia affects both sexes, was to explore the potential differences between male and female animals of this model. Overall, results suggest that the administration of PCP (10 mg/kg subcutaneous) on postnatal days (PNDs) 7, 9, and 11 leads to persistent alterations in recognition memory of male and female C57BL/6 mice. Additionally, results concerning male PCP-treated mice indicate spatial memory deficits and a tendency to be less sociable. Moreover, data shows increased expression levels of the truncated isoforms of the TrkB receptor (TrkB-TC) in the PFC of PCP animals of both sexes. Hence, the main findings of this thesis support the translational value of the neonatal PCP mouse model, providing new insights of the pathophysiologic mechanisms underlying cognitive dysfunction in schizophrenia and also unveil certain differences between male and female animals of this model.