Browsing by Subject "cytokine release"

Schizophrenia (SCZ) is a chronic neuropsychiatric disorder believed to arise from the intricate interplay between genetic predisposition and environmental factors. Though the aetiology of SCZ is unknown many findings support an excessive synaptic pruning hypothesis. Maternal immune activation (MIA), encompassing prenatal infection and systemic inflammation, constitutes a significant environmental risk factor implicated in SCZ onset (Patterson, 2009; Brown, 2012). MIA induces persistent alterations in the microglia of offspring termed microglial priming, characterized by heightened reactivity to inflammatory stimuli (Choudhury and Lennox, 2021). Notably, studies have reported increased sensitivity to activation, elevated expression of inflammatory markers, and an increase in the total number of microglia (Perry and Holmes, 2014; Choudhury and Lennox, 2021). Primed microglia may contribute to excessive synaptic pruning, thereby compromising neuronal connectivity and potentially leading to the onset of SCZ. This thesis investigated the impact of microglia on neurons and explored the microglial tendency for hyperactivation in the context of SCZ predisposition. It utilized induced pluripotent stem cell (iPSC) technology to create a rat astrocyte/unaffected control human iPSC-derived neuron/induced microglia-like cell (iMGL) tri-culture model. Uniquely, iMGLs were differentiated from a library of monozygotic twin lines discordant for SCZ, and unaffected controls. This allows for exploration of the differences between iMGLs from unaffected twins with a genetic predisposition for SCZ, affected twins with clinical manifestation of SCZ, and unaffected controls without a known genetic predisposition for SCZ. The tri-culture system was subjected to lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (poly(I:C)) treatments to activate iMGLs, and differences in cytokine release, synapse pruning, and neuronal activity were assessed. The principal outcomes of our investigation revealed enhanced cytokine release from SCZ-derived iMGLs when exposed to inflammatory stimuli, alongside increased network connectivity among samples containing genetically predisposed iMGLs. While most of the results did not reach significance, they suggest a potential link between SCZ pathophysiology and hyperactive microglia. Future research will focus on enlarging the study cohort, establishing tri-culture models featuring neurons and iMGLs derived from the iPSCs of the same patient, conducting CBA analysis to confirm the elevated cytokines finding, and scrutinizing iMGL morphology.