A loss of mature microglial markers without immune activation in schizophrenia

• Published in: Glia Vol. 69; no. 5; pp. 1251 - 1267
• Main Authors: Snijders, Gijsje J. L. J., Zuiden, Welmoed, Sneeboer, Marjolein A. M., Berdenis van Berlekom, Amber, Geest, Astrid T., Schnieder, Tatiana, MacIntyre, Donald J., Hol, Elly M., Kahn, René S., Witte, Lot D.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.05.2021; Wiley Subscription Services, Inc
• Subjects: Alzheimer Disease; Alzheimer's disease; Biomarkers; Brain; Cell density; Cortex (temporal); CX3CR1 protein; Cytology; Density; Disorders; Gene expression; Gene Expression Profiling; Genomes; Humans; Hypotheses; Immune response; Immune system; immunology; Mental disorders; Microglia; Microglial cells; Morphology; Neurodegenerative diseases; Pathogenesis; Phenotypes; postmortem; Schizophrenia; Schizophrenia - genetics; Transcriptomes; schizophrenia; postmortem; immunology; microglia; gene expression
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23962

Microglia, the immune cells of the brain, are important for neurodevelopment and have been hypothesized to play a role in the pathogenesis of schizophrenia (SCZ). Although previous postmortem studies pointed toward presence of microglial activation, this view has been challenged by more recent hypothesis‐driven and hypothesis‐free analyses. The aim of the present study is to further understand the observed microglial changes in SCZ. We first performed a detailed meta‐analysis on studies that analyzed microglial cell density, microglial morphology, and expression of microglial‐specific markers. We then further explored findings from the temporal cortex by performing immunostainings and qPCRs on an additional dataset. A random effect meta‐analysis showed that the density of microglial cells was unaltered in SCZ (ES: 0.144 95% CI: 0.102 to 0.390, p = .250), and clear changes in microglial morphology were also absent. The expression of several microglial specific genes, such as CX3CR1, CSF1R, IRF8, OLR1, and TMEM119 was decreased in SCZ (ES: −0.417 95% CI: −0.417 to −0.546, p < .0001), consistent with genome‐wide transcriptome meta‐analysis results. These results indicate a change in microglial phenotype rather than density, which was validated with the use of TMEM119/Iba1 immunostainings on temporal cortex of a separate cohort. Changes in microglial gene expression were overlapping between SCZ and other psychiatric disorders, but largely opposite from changes reported in Alzheimer's disease. This distinct microglial phenotype provides a crucial molecular hallmark for future research into the role of microglia in SCZ and other psychiatric disorders. Main Points Microglia density is unaltered in postmortem brain tissue of schizophrenia patients, but several mature microglial markers are downregulated in schizophrenia. This expression pattern is largely opposite from microglial changes in Alzheimer's disease.