A loss of mature microglial markers without immune activation in schizophrenia

Abstract

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.

Distinct trans-placental effects of maternal immune activation by TLR3 and TLR7 agonists: implications for schizophrenia risk

“…It is interesting that increased Aif1 mRNA expression, along with decreased expression of Cx3cr1 and Tmem119 mRNAs, has recently been reported in post-mortem temporal cortex from people with schizophrenia 102 . This parallels the changes we observe after maternal resiquimod administration.…”

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

“…indicating reduced microglia marker expression in bipolar disorder. Our findings of unchanged microglia marker expression in schizophrenia compared to controls but reduced microglia marker expression in the high inflammation schizophrenia subgroup suggests that findings of reduced microglia markers across other brain regions in schizophrenia may be exacerbated if cases were classified into inflammatory subgroups [ 21 ]. Microglia have a unique phenotype in the SEZ.…”

“…Therefore, the brain-resident immune cells, microglia, have been investigated in psychiatric disorders with varying results [ 19 , 20 ]. Microglia density is unaltered and various microglia-specific markers are often decreased across brain regions in schizophrenia [ 21 ]. In bipolar disorder, microglia density and mRNA levels of microglia markers are unchanged in the medial frontal gyrus [ 22 ].…”

Beyond Activation: Characterizing Microglial Functional Phenotypes

“…In rodents, another metabolic condition was shown to have an impact on microglial IBA1 expression: In the cingulate regions of the anterior corpus callosum and the hippocampus, a decrease in IBA1 expression was observed in long-term hypercorticosteronemia [23]. In patients suffering from schizophrenia, co-localization analysis showed significantly fewer microglia that were positive for IBA1 and TMEM119 in the temporal cortex, and also a decrease in the gene expression of several other microglial markers [24]. Recently, a loss or decrease of IBA1 expression was described in neurodegenerative diseases.…”

“…In patients suffering from schizophrenia, co-localization analysis showed significantly fewer microglia that were positive for IBA1 and TMEM119 in the temporal cortex, and also a decrease in the gene expression of several other microglial markers [ 24 ]. Recently, a loss or decrease of IBA1 expression was described in neurodegenerative diseases.…”