- Title
- Post-transcriptional gene regulation in schizophrenia, antipsychotic drug treatment and the developing brain
- Creator
- Santarelli, Danielle Maree
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2013
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Schizophrenia is a highly complex and debilitating neurodevelopmental disorder characterised by various physical and biochemical disturbances in the brain. Genetic risk is complex, including a collection of alterations to the genome and gene expression that are highly heterogeneic. Many affected genes are involved in pathways relevant to schizophrenia and tend to be downregulated. This has lead to focus on abnormalities of gene regulatory mechanisms, such as short non-coding RNA known as microRNA (miRNA), due to their ability to coregulate multitudes of genes and their importance in orchestrating neurodevelopment. In this study, miRNA expression was investigated in post-mortem brain from schizophrenia and control subjects. Global miRNA upregulation and upregulation of the biogenesis gene Dicer was observed. Gene expression was also investigated in this cohort. Downregulation of schizophrenia candidate genes and those with schizophrenia-relevant biological implications was observed. A significant schizophrenia-relevant miRNA-gene regulatory network was also identified. Alternatively, miRNA expression was profiled in the brain of healthy subjects spanning the neonate through to adult stages. A distinct divergence of decreasing miRNA and a smaller set of increasing miRNA from the teenage years was observed that opposes the global upregulation observed in schizophrenia subjects. miRNA expression was also investigated in mouse brain after antipsychotic drug (APD) treatment. Downregulation of small sets of miRNA that may play a role in the antipsychotic mechanism were observed. The altered miRNA of the atypical APDs were also associated with functions relevant to their metabolic side effects. A significant miRNA-gene regulatory network was identified in the olanzapine treatment group with neurological and metabolic implications. These findings collectively provide significant support for miRNA expression deviation from the normal expression pattern in the pathophysiology of schizophrenia, via dysregulation of gene expression and downstream neurological functions and pathways. This may have future implications in molecular diagnosis of schizophrenia and treatment via miRNA targeting or improvement of current drugs by considering individual heterogeneity in gene and miRNA expression and the possible role for miRNA in the antipsychotic mechanism.
- Subject
- schizophrenia; microRNA; psychosis; antipsychotic drugs; molecular neurobiology; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1037446
- Identifier
- uon:13439
- Rights
- Copyright 2013 Danielle Maree Santarelli
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
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| View Details Download | ATTACHMENT01 | Abstract | 328 KB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Thesis | 20 MB | Adobe Acrobat PDF | View Details Download |