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

Abstract

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.

Emerging evidence for astrocyte dysfunction in schizophrenia

“…Many studies have not actually investigated the status of astroglial cells during postnatal brain development, but were limited to the postmortem examination of adult brain tissues where dysregulation evident in developing astroglial cells are hidden, whereas this may have profound effects on the formation and maturation of neuronal networks. In line with this hypothesis, recent studies of in vitro cultures of human glial progenitors taken from SCZ patients has shown that the genes associated with glial differentiation in particular those associated with early oligodendroglial and astroglial lineage progression and those encoding for glia-derived metalloproteinases, were disrupted, thus indicating the existence of a cell autonomous glial pathology (Szabo et al, 2021;Windrem et al, 2017).…”

Contribution of astrocytes to familial risk and clinical manifestation of schizophrenia

“…Nevertheless, our study suggests that such differences may well occur at least in the subset of SCZ patients. Importantly, abnormalities in ECM have been among the strongest findings in iPSC‐derived brain cells already in three datasets (Kathuria et al, 2019 ; Szabo et al, 2021 ; Tiihonen et al, 2021 ), highlighting its importance in the pathophysiological process of SCZ. The reproducible results suggest the intriguing possibility that SCZ may be primarily a disease of ECM of the brain: abnormal and insufficient cell adhesion and ECM may result into abnormal neuron guidance and synaptogenesis, leading to imbalance in GABA/glutamate balance, and, finally, to clinical symptoms.…”

Patient iPSC-derived astrocytes with high polygenic risk for schizophrenia reveals a role for mitochondrial glutamate carrier SLC25A18

“…We hypothesize that glutamate metabolism is altered in SCZ cultures and could be the source of the phenotype seen in the current study. In accordance, SCZ iPSC-derived astrocytes have been shown to decrease glutamate uptake (30). Further research will have to con rm a potential causal role for GC2 in the altered glutamate clearance currently seen in SCZ and potentially even in the synaptic imbalance of the disorder.…”

“…Astrocytes were derived from the iPSCs according to our previously published protocol (30,(40)(41)(42) Neuronal differentiation…”

“…1A). iPSCs derived from all patients and controls were differentiated towards astrocytes using a previously published protocol (30,(40)(41)(42). To test for successful differentiation into the astrocytic lineage and potential difference between control and SCZ lines, we processed differentiation day 90 cells for immunocytochemical (ICC) labeling with astrocyte-associated markers CD44 (Fig.…”