A human iPSC-astroglia neurodevelopmental model reveals divergent transcriptomic patterns in schizophrenia

While neurodevelopmental abnormalities have been associated with schizophrenia (SCZ), the role of astroglia in disease pathophysiology remains poorly understood. In the present study, we used a human induced pluripotent stem cell (iPSC)-derived astrocyte model to investigate the temporal patterns of astroglia differentiation during developmental stages critical for SCZ using RNA sequencing. The model generated astrocyte-specific gene expression patterns during differentiation that corresponded well to astroglia-specific expression signatures of in vivo cortical fetal development. Using this model we identified SCZ-specific expression dynamics, and found that SCZ-associated differentially expressed genes were significantly enriched in the medial prefrontal cortex, striatum, and temporal lobe, targeting VWA5A and ADAMTS19. In addition, SCZ astrocytes displayed alterations in calcium signaling, and significantly decreased glutamate uptake and metalloproteinase activity relative to controls. These results implicate novel transcriptional dynamics in astrocyte differentiation in SCZ together with functional changes that are potentially important biological components of SCZ pathology.

Automated summary

This study investigated the temporal patterns and functional changes of astroglia differentiation in schizophrenia using a human iPSC-derived astrocyte model. The results revealed SCZ-specific gene expression dynamics in astrocytes, with enrichment of differentially expressed genes targeting VWA5A and ADAMTS19 in specific brain regions. SCZ astrocytes also showed alterations in calcium signaling, glutamate uptake, and metalloproteinase activity compared to controls, suggesting potential biological components of SCZ pathology.