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Abstract
Schizophrenia is a severe and disabling brain disorder, characterized by positive and negative symptoms, and cognitive impairments. Brain-derived neurotrophic factor (BDNF) plays an important role in neuroplasticity and has been proposed as a pathogenic factor in schizophrenia. Alterations in BDNF at the gene and protein level may contribute to altered brain physiology and may explain some of the cognitive, morphological and functional abnormalities observed in people with schizophrenia. A multidisciplinary approach integrating genetics, neuroimaging, molecular biology and cognition may help to better illuminate how BDNF contributes to the manifestation of schizophrenia. This thesis presents the results of three studies examining the relationship of BDNF to a number of core deficits and brain abnormalities routinely described in schizophrenia. First, BDNF val66met genotype was determined in a group of healthy participants displaying varying expression of schizotypal personality traits, and who were assessed on a measure of frontal-striatal dependent probabilistic association learning. People who expressed a high degree of schizotypal personality traits and the BDNF met allele displayed significantly worse probabilistic association learning, suggesting a role for the BDNF genotype in frontal-striatal learning in the context of schizophrenia-like traits. In the second study, people with schizophrenia were compared to healthy controls during probabilistic association learning while receiving functional Magnetic Resonance Imaging. In this study, healthy controls showed a positive relationship between peripheral BDNF levels and frontal-striatal neural activity, whereas no such relationship was demonstrated in people with schizophrenia. Finally, the potential influence of the BDNF val66met polymorphism on plasma BDNF levels, cognition and brain volume was assessed in people with schizophrenia and healthy controls. Plasma BDNF was positively related to hippocampal volume in healthy females and there were increased caudate volumes in females with schizophrenia who were BDNF met-carriers. These three studies provide evidence for the role of BDNF in the manifestation of selected cognitive deficits and morphological changes found in schizophrenia and for a role in frontal-striatal function in healthy adults.