Investigations of Olfactory Stem Cells in Schizophrenia
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Schizophrenia is a severely debilitating psychiatric disorder with a complex aetiology where aberrant expression of multiple genes, concurrent with neurodevelopmental events, is believed to lead to the disorder. The ability to biopsy and culture olfactory neuroepithelium from patients with schizophrenia may provide a window into the processes underlying the altered brain development and function in the disorder. It has been established that neurogenesis, the formation of new neurons, occurs throughout life. There are several lines of evidence suggesting adult neurogenesis may be affected in schizophrenia. The functional relevance of neurogenesis in the adult mammalian brain remains unknown, however a disruption of neurogenesis during early development is consistent with the neurodevelopmental hypothesis of schizophrenia. The presence of a neural stem cell has been established in the olfactory neuroepithelium, which can give rise to various neural populations, providing a valuable source for studying various aspects of neurogenesis. The aim of this study was to investigate the utility of olfactory stem cell lines in studying the processes underlying altered brain development and brain functioning in schizophrenia. We also investigated the skin fibroblast cell model, to assess the utility of non-neural cells in studying schizophrenia. A mitochondrial dysfunction and increased oxidative stress have been linked to patients with schizophrenia, and have been proposed to be involved in the pathophysiology of the disorder. We compared gene expression, neural differentiation, mitochondrial function and focal adhesion in cells from patients with schizophrenia and healthy controls. Our results showed significant disruptions of signaling pathways important in adhesion, cell communication and signaling in the olfactory stem cell lines from the patients group, and no significant pathway disrupted in the skin fibroblasts. Though both cell models indicated a focal adhesion dysfunction in schizophrenia, we found that olfactory stem cell lines show signs of a more severe dysregulation when compared to skin fibroblasts, which may reflect the differing structural roles of fibroblasts compared to neural cells. There was also an impaired oxidative stress response in both cell models, and also a mitochondrial dysfunction in the olfactory stem cell lines, phenomena which support the hypothesis that mitochondrial dysfunction and oxidative stress are involved in schizophrenia pathophysiology. Significantly, differences in differentiation between patient and control groups were revealed. Altered neurogenesis in cells from patients with schizophrenia, support our other hypothesis that adult neurosgenesis is involved in schizophrenia pathophysiology. Though the details of adult neurogenesis, focal adhesion, mitochondrial function and oxidative stress remain to be elucidated in schizophrenia, these findings together with their proposed roles in brain function make them relevant to schizophrenia research. While we found that fibroblasts are not informative as a cell model for schizophrenia, we conclude that olfactory stem cell lines are a promising tool for studying neurobiological aspects of schizophrenia.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical and Physical Sciences
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