Inflammation-related transcripts define “high” and “low” subgroups of individuals with schizophrenia and bipolar disorder in the midbrain

Abstract

Dopamine dysregulation in schizophrenia may be associated with midbrain inflammation. Previously, we found elevated levels of pro-inflammatory cytokine mRNAs in the post-mortem midbrain of people with schizophrenia (46%) but not from unaffected controls (0%) using a brain cohort from Sydney, Australia. Here, we measured cytokine mRNAs and proteins in the midbrain in the Stanley Medical Research Institute (SMRI) array cohort (N = 105). We tested if the proportions of individuals with schizophrenia and with high inflammation can be replicated, and if individuals with bipolar disorder with elevated midbrain cytokines can be identified. mRNA levels of 7 immune transcripts from post-mortem midbrain tissue were measured via RT-PCR and two-step recursive clustering analysis was performed using 4 immune transcripts to define “high and low” inflammatory subgroups. The clustering predictors used were identical to our earlier midbrain study, and included: IL1B, IL6, TNF, and SERPINA3 mRNA levels. 46% of schizophrenia cases (16/35 SCZ), 6% of controls (2/33 CTRL), and 29% of bipolar disorder cases (10/35 BPD) were identified as belonging to the high inflammation (HI) subgroups [χ2 (2) = 13.54, p < 0.001]. When comparing inflammatory subgroups, all four mRNAs were significantly increased in SCZ-HI and BPD-HI compared to low inflammation controls (CTRL-LI) (p < 0.05). Additionally, protein levels of IL-1β, IL-6, and IL-18 were elevated in SCZ-HI and BPD-HI compared to all other low inflammatory subgroups (all p < 0.05). Surprisingly, TNF-α protein levels were unchanged according to subgroups. In conclusion, we determined that almost half of the individuals with schizophrenia were defined as having high inflammation in the midbrain, replicating our previous findings. Further, we detected close to one-third of those with bipolar disorder to be classified as having high inflammation. Elevations in some pro-inflammatory cytokine mRNAs (IL-1β and IL-6) were also found at the protein level, whereas TNF mRNA and protein levels were not concordant.