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.
Following the decline of neurogenesis at birth, progenitors of the subventricular zone (SVZ) remain mostly in a quiescent state in the adult human brain. The mechanisms that regulate this quiescent state are still unclear. Here, we isolate CD271+ progenitors from the aged human SVZ for single-cell RNA sequencing analysis. Our transcriptome data reveal the identity of progenitors of the aged human SVZ as late oligodendrocyte progenitor cells. We identify the Wnt pathway antagonist SFRP1 as a possible signal that promotes quiescence of progenitors from the aged human SVZ. Administration of WAY-316606, a small molecule that inhibits SFRP1 function, stimulates activation of neural stem cells both in vitro and in vivo under homeostatic conditions. Our data unravel a possible mechanism through which progenitors of the adult human SVZ are maintained in a quiescent state and a potential target for stimulating progenitors to re-activate.
Following the decline of neurogenesis at birth, progenitors of the subventricular zone (SVZ) remain mostly in a quiescent state in the adult human brain. The mechanisms that regulate this quiescent state are still unclear. Here, we isolated CD271+ progenitors from the aged human SVZ for single-cell RNA sequencing analysis. Our transcriptome data revealed the identity of progenitors of the aged human SVZ as late oligodendrocyte progenitor cells. We identified the Wnt pathway antagonist SFRP1 as a possible signal that promotes quiescence of progenitors from the aged human SVZ. Administration of WAY-316606, a small molecule that inhibits SFRP1 function, stimulates activation of neural stem cells both in vitro and in vivo under homeostatic conditions. Our data unravel a possible mechanism through which progenitors of the adult human SVZ are maintained in a quiescent state and a potential target for stimulating progenitors to re-activate.
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