A schizophrenia subgroup with elevated inflammation displays reduced microglia, increased peripheral immune cell and altered neurogenesis marker gene expression in the subependymal zone

Hayley F North,Christin Weissleder,Janice M Fullerton,Rachel Sager,Cynthia Shannon Weickert,Maree J Webster

doi:10.1038/s41398-021-01742-8

Abstract

Inflammation regulates neurogenesis, and the brains of patients with schizophrenia and bipolar disorder have reduced expression of neurogenesis markers in the subependymal zone (SEZ), the birthplace of inhibitory interneurons. Inflammation is associated with cortical interneuron deficits, but the relationship between inflammation and reduced neurogenesis in schizophrenia and bipolar disorder remains unexplored. Therefore, we investigated inflammation in the SEZ by defining those with low and high levels of inflammation using cluster analysis of IL6, IL6R, IL1R1 and SERPINA3 gene expression in 32 controls, 32 schizophrenia and 29 bipolar disorder cases. We then determined whether mRNAs for markers of glia, immune cells and neurogenesis varied with inflammation. A significantly greater proportion of schizophrenia (37%) and bipolar disorder cases (32%) were in high inflammation subgroups compared to controls (10%, p < 0.05). Across the high inflammation subgroups of psychiatric disorders, mRNAs of markers for phagocytic microglia were reduced (P2RY12, P2RY13), while mRNAs of markers for perivascular macrophages (CD163), pro-inflammatory macrophages (CD64), monocytes (CD14), natural killer cells (FCGR3A) and adhesion molecules (ICAM1) were increased. Specific to high inflammation schizophrenia, quiescent stem cell marker mRNA (GFAPD) was reduced, whereas neuronal progenitor (ASCL1) and immature neuron marker mRNAs (DCX) were decreased compared to low inflammation control and schizophrenia subgroups. Thus, a heightened state of inflammation may dampen microglial response and recruit peripheral immune cells in psychiatric disorders. The findings elucidate differential neurogenic responses to inflammation within psychiatric disorders and highlight that inflammation may impair neuronal differentiation in the SEZ in schizophrenia.

Highlights

Schizophrenia and bipolar disorder are severe psychiatric disorders with unknown causes affecting ~1% [1] and ~3% [2] of the population, respectively
Cohort demographics by diagnosis and relationships for Inflammatory marker expression was increased in the subependymal zone (SEZ) in a subgroup of cases with schizophrenia and bipolar disorder To determine the percentage of cases defined as high and low inflammation in the SEZ in psychiatric disorders compared to unaffected controls, we measured mRNA expression of cytokines, their receptors and other inflammation-associated genes
IL1 receptor 1 (IL1R1) mRNA was significantly different across diagnostic groups [Supplementary Fig. S1, ANCOVA (RIN), F(2,84) = 4.28, p = 0.017], with increased expression in schizophrenia (62%, p = 0.004) but not in bipolar disorder compared to controls (p = 0.14)

Summary

Introduction

Schizophrenia and bipolar disorder are severe psychiatric disorders with unknown causes affecting ~1% [1] and ~3% [2] of the population, respectively. Both disorders have common characteristics, such as the presence of psychosis [3], cognitive [4] and negative symptoms [5], and overlapping genetic risk [6,7,8]. To account for the heterogeneous molecular profile within psychiatric disorders, recent studies use cluster analysis to determine subgroups within schizophrenia and bipolar disorder

Results

Discussion

Conclusion