Microglia in psychiatric disorders: A search for immune activation

Abstract

The involvement of the immune system has been implicated in the aetiology of schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). Although previous research supports immune alterations in SCZ, BD, and MDD, less is known about how the immune system is involved in causing brain dysfunction in these disorders. Since microglia are the immune cells of the central nervous system (CNS), it is hypothesized that these cells contribute to the pathophysiology of SCZ, BD, and MDD. Therefore, the aim of this thesis was to elucidate the role of microglia, and more specifically their immune activating properties, in SCZ, BD, and MDD by using a multi-level approach. For our research purposes, we established a protocol to isolate human microglia from post-mortem human brain tissue and generated a cryopreservation protocol to study microglial proteins. With CyTOF we showed that specific microglial phenotypic signatures exist in various brain regions. Furthermore, we found that TSPO is not differently expressed in post-mortem tissue of patients with SCZ compared to controls. Moreover, we showed that SCZ lacks the hallmarks of neuroinflammation (e.g. microglial activation) and cannot be seen as a classic neuroinflammatory disorder. Finally, we found no inflammatory profile of the ex vivo isolated microglia from patients with BD and MDD, although decreased expression of pathways involved in cell cycle and cell division were found in MDD microglia. Overall we could not find evidence of an immune activated microglial profile in all three disorders. However, other non-immune functions of microglia can still contribute to the disorders. Future studies to unravel the biological mechanism underlying SCZ, BD and MDD should focus more on microglia-neuron communication, the specific role of microglia in neurogenesis and synaptic pruning, and the effect of genetic and environmental factors on these cells.