NEUROIMMUNE MODULATION IN SCHIZOPHRENIA: INVESTIGATING THE PRESENCE OF ALTERED MICROGLIAL PHENOTYPES AND THEIR RESPONSE TO ANTIPSYCHOTIC TREATMENT

Background: Microglia are the main resident immune cells of the brain, contributing to its development, protection and homeostasis. Given the versatility of microglia's roles, disruptions in microglia functioning have been implicated in the pathophysiology of schizophrenia. While antipsychotics, the main treatment for schizophrenia, are believed to exert immunomodulatory effects, their precise impact on microglia remains unknown.
Aims: This study aimed to characterize molecular and functional profiles of human induced pluripotent stem cell (hiPSC)–derived microglia from schizophrenia patients relative to healthy controls, and to assess how acute antipsychotic exposure modulates these phenotypes.
Methods: hiPSCs from schizophrenia patients (n=4) and healthy controls (n=4) were differentiated into microglia-like cells. A pilot dose–response study evaluated the effects of clozapine, olanzapine, and haloperidol (0–1000 nM) on cell viability and cytotoxicity to guide dose selection. Microglia were subsequently treated for 24 hours with clozapine (1 μM), haloperidol (50 nM), olanzapine (100 nM), or vehicle (DMSO). Functional assays included motility and phagocytosis assessment, cytokine profiling and bulk RNA-sequencing.
Results: Neither diagnosis nor antipsychotic treatment influenced microglial phagocytic capacity or motility. Qualitative cytokine profiling suggested elevated baseline SERPINE1 secretion in patient-derived microglia, further enhanced following clozapine and haloperidol exposure. Transcriptomic analyses are ongoing.
Conclusion: Overall, these findings indicate that acute antipsychotic exposure does not alter key functional microglial phenotypes in monoculture, and that disease-relevant microglial differences may require neuronal context to be unmasked. Future work will employ hiPSC-derived microglia–neuron co-culture systems to investigate how cellular interactions shape microglial behaviour in schizophrenia.