The role of miRNA and post-transcriptional gene silencing in mediating the mammalian brain’s response to environmental stress during development and ageing

Research Doctorate - Doctor of Philosophy (PhD)Schizophrenia is a severely debilitating, complex neuropsychiatric disorder characterised by a diverse range of symptoms. It is considered to be a disorder of neurodevelopment, attributable to the action and interaction of multiple genes, as well as with environmental factors. These interactions are thought to influence neurodevelopmental processes leading to abnormalities in brain plasticity and connectivity and ultimately to schizophrenia in early adulthood. Despite a clear genetic component and high degree of heritability, no single gene has been found to be responsible for the onset of the disorder. Moreover, evidence indicates a systematic regulatory dysfunction of gene expression in schizophrenia, suggesting extensive posttranscriptional regulation of gene expression during neural development. MicroRNA (miRNA) post-transcriptionally modulate gene expression by either repressing translation or inducing mRNA degradation, placing them in an ideal position to drive the widespread translational disturbances that are observed in the disorder. Disruptions in the biogenesis of miRNA have been observed in schizophrenia and it is plausible that these changes may be related to major environmental risk factors associated with the disorder, such as maternal immune activation (MIA) and adolescent cannabis use (ACE). To investigate the role of miRNA in neurodevelopment and in response to environmental stress, whole genome microarrays were used to elucidate miRNA and mRNA expression throughout neurodevelopment and in response to MIA and ACE. These studies identified an important role for miRNA in the development of the mammalian brain, a complex dynamic process requiring precise regulation of both temporal and spatial gene expression. Throughout neurodevelopment, miRNA expression was found to be region and time specific with an important influence in functionally relevant pathways in the developing brain, highlighting their potential significance in the etiology and pathophysiology of neuropsychiatric disorders such as schizophrenia. MiRNAs in the central nervous system play an important regulatory role in fundamental processes and therefore the impact of any abnormality, particularly ones occurring during vital developmental periods, could have profound clinical implications. Determining both the temporal and spatial differences in miRNA and gene expression during this period allows the prediction of neurodevelopmental events and identification of differing windows of vulnerability to environmental insults. Evidence indicates that schizophrenia is a disorder of both early and late brain development to which genetic and environmental influences contribute. To understand the role of miRNA in the brain’s response to both and early (MIA) and late (ACE) environmental insult, miRNA and gene expression was examined in the entorhinal cortex (EC), a brain region shown to display altered volumes and other anatomical abnormalities in schizophrenia. The interaction of MIA and ACE was found to significantly alter miRNA expression, whereas only a small effect was observed for each treatment alone. This effect occurred predominantly in the left hemisphere and was dominated by a large subgroup of miRNA differentially transcribed from a single imprinted locus on chromosome 6q32. In humans, the syntenic locus (14q32) encodes a large proportion of miRNAs previously identified as differentially expressed in schizophrenia. Changes in miRNA expression correlated with alterations in gene expression, with genes identified as potentially regulated by differentially expressed miRNA predicted to encode proteins with prominent functions in neuronal growth and differentiation; development of specific cortical layers; synaptic plasticity and transmission; axonogenesis; gamma-aminobutyric acid (GABA) neurotransmitter system; and learning and memory formation. The findings presented in this thesis provide evidence that miRNA have important roles throughout neurodevelopment that are both region- and time-specific. In addition, it was established that the interaction of both an early and late environmental insult alters miRNA and gene expression in the EC with possible outcomes relevant to schizophrenia in adulthood