Microglia/Macrophage Transcripts Are Increased in Neuroinflammatory Schizophrenia and Bipolar Disorder Midbrains

Background We have previously found increased microglial/macrophage transcripts in the midbrains of people with schizophrenia that display a high-inflammation profile. However, contradictory results of decreased and unchanged markers have also been reported in other brain regions of schizophrenia and bipolar disorder. It is known that the mammalian midbrain contains a more active and higher population of microglial cells than other brain regions, making it more susceptible to inflammatory insults. In our earlier studies, we found that molecular markers of microglia/macrophage increases were exaggerated in the midbrains of highly-inflamed schizophrenia. Aims & Objectives Here, we sought to replicate these observations in a new cohort and to compare them to microglia/macrophage markers measured in bipolar cases with low and high-inflammation states. We hypothesized that markers of microglial function including activation and phagocytosis would be elevated in high-inflammation schizophrenia and bipolar disorder. Method Normalized mRNA levels of eleven microglial/macrophage markers were measured and compared via reverse transcriptase-quantitative PCR from human post-mortem midbrains of 61 healthy controls, 63 schizophrenia, and 33 bipolar disorder cases. Results Overall, mRNA markers associated with microglial/macrophage movement were significantly increased in schizophrenia (IBA1, CD11B; all p≤0.001) and significantly decreased in bipolar disorder (P2RY12, CX3CR1; all p≤0.01) high-inflammation compared to controls. mRNA markers associated with antibody/IgG microglial/macrophage activation were significantly increased in schizophrenia (FcGRI/CD64 & FcGRIIc/CD32C) and bipolar disorder (FcGRIIc/CD32C) high-inflammation compared to controls (all p≤0.01). mRNA expression of CD40, a microglial/macrophage marker associated with cytokine release was significantly increased in high-inflammation schizophrenia and bipolar disorder compared to controls (all p≤0.001). Lastly, mRNA expression of CD68, a microglial/macrophage marker associated with phagocytosis was significantly increased in high-inflammation schizophrenia compared to controls (p≤0.0001). Discussion & Conclusions Our results show transcriptionally shared antibody receptor, cytokine release and phagocytosis increases, suggesting activation of microglial/macrophages in the midbrains of people with schizophrenia and bipolar disorder with elevated inflammation. We also found a few distinct microglial/macrophage transcriptional-based changes between these two psychotic disorders, suggesting that there may be specific subpopulations of microglia impacted differentially. These findings help to address differences in immune cell activity between schizophrenia and bipolar disorder and pinpoint potential immune-based cell targets for future neuropharmacological treatments.