Understanding the Predisposition and Emergence of Schizophrenia using Animal and In Vitro Models: Implicating Immune-Related Signalling and Synaptic Structure and Function

Schizophrenia is a chronic, debilitating mental illness characterised by psychosis, negative apathetic symptoms and cognitive deficits. Although the exact neurobiology underpinning schizophrenia remains poorly understood, there are multiple lines of evidence implicating neurochemical disruptions, morphological brain changes and genetic or epigenetic risk factors. Current therapies for the treatment of schizophrenia are limited in their ability to treat all symptom domains, as well as their unfortunate side effect profile. Therefore, the overall aim of this body of work was to improve the understanding of the underlying pathophysiology of the disease, by using animal models and in vitro cultures, to bridge the gap toward better treatment options. Transcriptomic analysis of two neuropsychiatric models, maternal deprivation and isolation rearing, identified a core immune-related cluster that potentially related to both predisposition and emergence of psychosis via in silico analysis. The relationship of this gene cluster to the schizophrenia disease process was confirmed using an iPSC-derived human co-culture model of neurons and microglia, by identifying a direct link between the immune-related cluster and the synaptic pruning, or phagocytic, ability of microglia. Importantly, the in silico predicted regulator IRF7 was found to be central to this relationship, implicating IRF7 as a compelling target for future research. Thus, the results of this thesis implicate a temporal cascade of dysregulation that ultimately impinges on microglial-mediated synaptic pruning in an immune, but not necessarily inflammatory, manner. The clinical profile of schizophrenia is noted to differ largely in terms of symptom emergence and pharmacotherapy response across genders. However, the molecular reasons for these differences are mostly unexplored. In this thesis, using the isolation rearing model, we identified a number of stark differences between the two genders. Principally, we found that the isolated female animals exhibited changes in cytoskeletal and synaptic-related biologies much earlier in the disease process than the male cohort, reflecting the established gender-specific timeline of emergence. However, most strikingly, we also observed a novel across-gender dysfunction in glutamate signalling. We discovered temporal clusters which coregulated in both genders and impinged predominately on altered synaptic structure and function via glutamatergic signalling and potentially convergent microglial dysfunction. Thus, the findings in this thesis provide a unique context to directly link the well-established theory of synaptic dysfunction underpinning schizophrenia to both immune-related and glutamatergic dysfunction, across genders.