Transcriptional Modeling of Severe Mental Illnesses

Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses characterized by a heterogenous clinical presentation and a complex underlying pathophysiology which is not fully understood. Genetic studies have identified many risk variants, the majority of which are located within non-coding regions of the genome, suggesting primarily a role in gene expression regulation. In this thesis, microarrays and RNA sequencing were used for transcriptome profiling in various experimental models. The aim was to explore the transcriptional underpinnings of three clinical aspects of SCZ and BD: verbal memory, lithium treatment, and inflammatory modulation. Memory performance was inversely associated with peripheral TCN1 expression in both SCZ and BD. TCN1 is involved in vitamin B12 transportation and cellular uptake, and the finding may thus have important implications for the diagnosis and treatment of vitamin B12-related conditions. Lithium treatment in rodent brains was associated with the differential expression of GRIN2A, which encodes a subunit of glutamate-mediated NMDA receptors, the most important excitatory receptors in the brain. This finding lends support to the glutamatergic hypothesis of BD. Inflammatory modulation was associated with a reduced expression of CCL20 in astrocytes derived from SCZ patients. Astrocytes secrete the chemokine CCL20 to attract regulatory T cells to the site of inflammation in order to terminate the immune response, suggesting that a dysfunctional astrocyte-mediated recruitment of T cells may be involved in the over-active immune state seen in SCZ patients. In summary, we identify specific transcriptional mechanisms that may underlie the clinical aspects under study. Some of these findings have potential clinical relevance or may inform the development of novel therapeutic agents. These findings also further confirm that transcriptional mechanisms play a central role in the pathophysiology of SCZ and BD