Hippocampal Subfield Transcriptome Analysis in Schizophrenia Psychosis

Schizophrenia is one of the thirty most incapacitating conditions in the world and affects tens of millions of people worldwide. Devastatingly, suicide occurs in 10% of those diagnosed with schizophrenia. Symptoms are persistent and often severe and available treatments are not curative. In fact, 20-33% of people with schizophrenia are entirely resistant to treatment. The complex symptom manifestations of schizophrenia lack a molecular pathology. Consequently, advances in novel treatment directions are limited. Schizophrenia is recognized as a polygenic disorder influenced by environmental factors. This dissertation aims to examine this polygenic nature of this disorder. Genome wide association studies have identified hundreds of common genetic variants, which individually confer a small risk for schizophrenia. However, all identified genetic variants combined only account for a modest amount of the total heritability of schizophrenia. In this dissertation, I capitalize on the unique ability of next-generation sequencing to identify in a global and unbiased manner molecular changes, which have not been previously hypothesized, but may contribute to the origin of the missing heritability of schizophrenia and play a role in schizophrenia symptomatology. The Tamminga lab has particular interest in schizophrenia psychosis, conceptualizing it as a disorder of learning and memory, critically involving dentate gyrus (DG), CA3, and CA1 of the hippocampus. Therefore, this doctoral dissertation examines the transcriptome of all three subfields, DG, CA3, and CA1 in human postmortem tissue of controls and individuals diagnosed with schizophrenia, using RNA-seq to identify additional psychosis-mediating molecular candidates and produce plausible targets for therapeutic treatment. After Chapters 1, 2, and 3 introduce the significance and contribution of this dissertation to the field of neuroscience in psychiatry, I show (Chapter 4) that each hippocampal subfield in schizophrenia has a unique molecular identity based on its transcriptome profile. As well, I show only slight effects of antipsychotic medication on schizophrenia-dependent gene changes in DG, CA3, and CA1. Taken together, my data identify molecular candidates and specific cell populations that we previously did not hypothesize as potential contributors to schizophrenia pathology. Finally, in Chapter 5, I outline future directions based on the contributions of my doctoral dissertation to the field.