The role of Toll-like receptors and their relevance to cognition in schizophrenia – biological, transcriptomic and genomic data based evidence

Schizophrenia is a debilitating psychiatric disorder with a complex aetiology. Individuals with this disorder experience positive, negative, and cognitive symptoms. The literature, through decades of research, supports an immune hypothesis, suggesting cytokine imbalance in schizophrenia. However, a significant gap remains: the cause of this imbalance, which results in low-grade chronic inflammation, is still unknown. To fill this gap, in this thesis, I investigated one of the sources of cytokines, Toll-like receptors (TLRs). They belong to a family of pattern recognition receptors. These receptors are ubiquitously expressed and are highly expressed on immune cells (macrophages, dendritic cells, lymphocytes, microglia, and other cells). Activation of TLRs stimulates cytokine production. This thesis investigates the role of TLRs in schizophrenia using peripheral blood samples, their connection to cognition, genomic and transcriptomic changes, and the impact of antipsychotic drug dose on immune function and cognition. In this thesis, I found that TLRs are associated with cognitive deficits. I found that increased activity of TLRs leads to elevated cytokine levels in patients which in turn is associated with cognitive deficits. The genomics and transcriptomics studies also suggest a strong immune dysfunction in schizophrenia and implicate the potential role of TLRs in schizophrenia. While the associations of TLRs with cognition are modest, more longitudinal studies are required to increase the robustness of these results. Overall, the findings from this thesis suggest that the role of TLRs extends beyond the immune system, and changes in their activity, expression, and gene sequence have broader implications, potentially affecting cognition. This thesis provides an empirical basis for carrying out further investigations into the role of TLRs in schizophrenia and the underlying mechanisms that connect TLRs to cognition in humans.

Publisher

University of Galway

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CC BY-NC-ND

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University of Galway Theses (PhD Theses)