Midbrain microglial and macrophage mRNAs distinguish neuroinflammatory schizophrenia from bipolar disorder.

Increased microglial/macrophage transcripts are found in the midbrains of people with a neuroinflammatory subtype of schizophrenia. However, it is unknown in which immune cell population these transcripts are mostly expressed, nor do we know if transcriptional changes in microglial/macrophage markers are also found in the midbrain of neuroinflammatory bipolar disorder. Here, we determined the extent of microglial/macrophage changes in the ventral midbrain (at the level of the oculomotor nerve exit) of a large cohort of people with schizophrenia and bipolar disorder, defined as either low or high-inflammation, compared to controls. We aimed to confirm in which cell-type cluster our transcripts were expressed (microglia vs macrophages). First, we mapped the cellular expression of putative microglial/macrophage markers via snRNA-seq. Then, mRNA levels of 11 microglial/macrophage markers were measured and compared via RT-PCR from human post-mortem midbrains of 61 healthy controls, 63 schizophrenia cases, and 33 bipolar disorder cases. 7/11 mRNAs (IBA1, CD11B, CX3CR1, P2RY12, CD64, CD40, & TMEM119) were mainly expressed in microglial cell clusters; 2 mRNAs were in the macrophage cell cluster (CD32C, CD86); 1 mRNA was broadly expressed (HEXB), and CD68 mRNA was too low to confirm cellular source by snRNA-seq. Across groups, transcripts associated with microglia activation and motility were significantly increased in high-inflammation schizophrenia (IBA1, CD11B; all p ≤ 0.001) and significantly decreased in high-inflammation bipolar disorder (P2RY12, CX3CR1; all p ≤ 0.01) compared to low-inflammation controls. Transcripts associated with microglial and macrophage activation via FcγR-IgG/Immune complex antigen binding were significantly increased in high-inflammatory schizophrenia (CD64 & CD32C) and high-inflammatory bipolar disorder (CD32C) (all p ≤ 0.01). Transcripts associated with increased cytokine response (CD40 & CD86) and phagocytosis (CD68) were significantly increased in high-inflammatory schizophrenia and divergently changed in high-inflammatory bipolar disorder (CD40 increased/CD86 decreased) (all p ≤ 0.05). Overall, the number of CD68 + cells with reactive-like morphology was increased in high-inflammation schizophrenia compared to all the low-inflammation groups (all p ≤ 0.05). Our findings strengthen the contention that microglia and macrophages are activated in schizophrenia and disrupted in bipolar disorder midbrains of high-inflammatory subgroups. This suggests that optimal immune-based treatments targeting schizophrenia and bipolar disorder patients may differ when restoring microglial function during inflammation.