For more than a century it has been suggested that the immune system is involved in the pathogenesis of schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). For example, researchers found changes in important genes of the immune system and increased expression of chemokines and cytokines (e.g. immune factors) in patients with a psychiatric disorder. It is clear that the immune system plays a role in these three disorders, but not exactly how. This thesis focusses on the microglia, the immune cells of the brain. These cells are essential as defense mechanism to diseases and clearing cellular debris in the brain. Moreover, they are highly involved in brain development by eliminating unnecessary neurons and stimulating the growth of new neurons. Until now there is not much known to what extent microglia are contributing to the pathogenesis of SCZ, BD, and MDD, but it is suggested that the microglia are overactive in their immune functions, resulting in the psychiatric symptoms.
The aim was to phenotype the microglia in these three disorders to study if they are different in patients with a psychiatric disorder compared to controls (people without a psychiatric disorder). We used a special technique in which primary microglia were isolated from post-mortem brain tissue of patients and controls. We showed that the isolated microglia are different from other human immune cells, such as monocytes, and that they will maintain their immune functions in culture (chapter 2). Additionally, we developed a method to preserve the protein expression of the cells directly after isolation. The benefit of this method was that the samples could be collected first and analyzed at the same time to diminish technical variation. With this method we discovered that the protein expression of the microglia were specific for the brain region they were isolated from (chapter 3).
In vivo, microglia are currently visualized with PET tracers for the TSPO protein. However, various independent studies reported an increased, decreased, or equal expression of TSPO in patients with SCZ. In post-mortem tissue we found a similar expression of TSPO in patients with SCZ and controls (chapter 4). Furthermore, TSPO was not directly related to increased immune activation of microglia. This suggests that TSPO might not be an accurate market to measure microglial activity in the brain of patients with SCZ. Next, we invalidated the hypothesis that SCZ is a neuroinflammatory disorder (chapter 5). We found no difference in the number of microglia or signs of immune activation in patients with SCZ. However, we observed more T-lymphocytes in the parenchyma of patients, which might be related to a change in genes involved in the interferon response.
In both BD and MDD we did not find indications of a microglial immune activated profile. The number of microglia was similar between controls and patients with BD, they displayed a ramified morphology (e.g. not immune activated), and their protein- and gene expression was comparable (chapter 6). We performed a large transcriptomic analysis on isolated microglia from patients with MDD and controls (chapter 7). In total we found 194 differentially expressed genes between patients and controls. 188 genes showed decreased expression in patients with MDD, whereas 6 genes were upregulated. The genes with the largest difference between patients and controls are playing a role in cell division and cell cycle, processes that were all decreased in MDD.
In summary, we concluded that the microglia in SCZ, BD, and MDD were not immune activated. However, this does not mean that the cells are not contributing to the disorders. Besides their immune regulatory functions, microglia are also involved in multiple other processes in the brain. For example, there are indications that the communication between neurons and microglia are disturbed. This might have direct influence on the elimination of neurons and the regulation of neurotransmitters. To unravel the underlying neurobiology of SCZ, BD, and MDD future research should focus on the communication between neurons and microglia, their specific role in neuronal development, and the effect of genetic and environmental factors on microglia.