Schizophrenia (SCZ) has a known neurodevelopmental etiology, but limited access to human prenatal brain tissue hampers the investigation of basic disease mechanisms in early brain development. Here, we elucidate the molecular mechanisms contributing to SCZ risk in a disease-relevant model of the prenatal human brain.
We generated induced pluripotent stem cell-derived cortical spheroids (hCSs) from a large and genetically stratified sample of 14 SCZ patients and 14 age and sex-matched controls (CTRL). The hCSs were differentiated for 150 days, and comprehensive molecular characterization across four time points was carried out.
The transcriptional and cellular architecture of hCSs closely resembled that of 10-24 post-conception week fetal brain, showing strongest spatial overlap with frontal regions of the cerebral cortex. A total of 3,520 genes were differentially modulated between SCZ and CTRL hCSs across organoid maturation, displaying a significant contribution of genetic loading, an over-representation of risk genes for autism spectrum disorder and SCZ, and strongest enrichment for axonal processes in all hCS stages. The two axon guidance genes SEMA7A and SEMA5A, the first a promoter of synaptic functions and the second a repressor, were down and up-regulated in SCZ hCSs, respectively. This expression pattern was confirmed at the protein level and replicated in a large post-mortem sample.
Applying a disease-relevant model of the developing fetal brain, we identified consistent dysregulation of axonal genes as an early risk factor for SCZ, providing novel insights into the effects of genetic predisposition on the neurodevelopmental origins of the disorder.
Copyright © 2023. Published by Elsevier Inc.
