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Abstract
Schizophrenia may result from aberrations in maturational neurodevelopmental processes. While many genetic and environmental factors increase the risk of schizophrenia, it is currently unclear how these factors interact across the course of adolescent development to result in the emergence of the illness during this period. New neurons are produced in the mammalian hippocampus through adolescence into adult life. Dysregulated hippocampal neurogenesis produces memory impairments that resemble those found in schizophrenia. In addition, factors that are known to regulate neurogenesis, including sex steroids and neurotrophins, have been identified as potential schizophrenia risk factors. However, there are few studies of neurogenesis in schizophrenia, and limited experimental studies on hormones and adolescent neurogenesis. This thesis investigated hippocampal cell proliferation in schizophrenia, and explored how adolescent testosterone influences neurogenesis and neurotrophin expression in the rat and monkey hippocampus. We hypothesised that cell proliferation would be reduced in the hippocampus in schizophrenia, and found a 60% decrease relative to controls, replicating the results of a previous study. We show for the first time that adolescent gonadectomy in monkeys increased neurogenesis via increasing cell survival and immature neurons. In contrast to existing studies in adult rats, two-week testosterone replacement in rat adolescence decreased cell proliferation. In young adult rats, testosterone had mixed and complex effects on cell proliferation and survival, which may underlie age-related changes in the influence of testosterone on neurogenesis. In monkeys and rats, the mechanism of action of testosterone on neurogenesis was not via changing mRNA levels of two key factors regulating new neuron proliferation and survival, brain-derived neurotrophic factor (BDNF) or its receptor (TrkB), but testosterone appears to modulate the relationship between cell proliferation and BDNF/TrkB signalling. Our results support the model that altered postnatal neurogenesis contributes to hippocampal pathology in schizophrenia and suggest that rising levels of testosterone at may act as a risk factor for the development of schizophrenia in predisposed individuals by decreasing postnatal neurogenesis during adolescence. However, it is clear that the influence of testosterone on neurogenesis is complex, and undergoes dynamic changes from adolescence to adulthood.