The molecular and cellular analysis of cell lines derived from patients with schizophrenia

Schizophrenia and other psychiatric disorders are highly polygenic and associated with large-scale perturbations in gene expression and broad reaching regulatory mechanisms such as posttranscriptional gene silencing by microRNAs (miRNAs). Environmental risk factors have also been suggested to contribute to the etiology of these diseases, but the underlying molecular mechanisms remain to be elucidated. This thesis aimed to, first, investigate the transcriptome changes, including gene and miRNA expression, in response to oxidative stress, a potential risk factor for mental illnesses, and then, look for candidate miRNA biomarkers with implication for cognitive dysfunction in schizophrenia patients. Our results in Chapters 2 and 3 demonstrate that exposure to oxidative stress before or during neural differentiation causes substantial dysregulation of a large number of genes enriched in neurodevelopmental and immune processes and diseases, a subset of which were potentially regulated by differentially expressed miRNAs associated with psychiatric disorders, including miR-137 and miR-181b. In Chapter 4, we observed a substantial reduction in the expression of miR-3175 in peripheral blood of schizophrenia cases with severe cognitive impairment compared to cognitively spared patients. Transfection of differentiated neuron-like cells with this miRNA mimic and inhibitor oligomers revealed its posttranscriptional influence on the expression of many genes related to the functions and diseases of the nervous and immune systems. Collectively, this thesis findings provide evidence of a plausible causal role in later life development of psychiatric diseases for prenatal exposure to oxidative stress, add more insight into the well-established link between immune system aberrations and neurodevelopmental disorders, and suggest miR-3175 as a new schizophrenia-associated miRNA with possible utility as a blood biomarker for cognitive impairment.