The following is a summary of “Recapitulation of Perturbed Striatal Gene Expression Dynamics of Donor’s Brains With Ventral Forebrain Organoids Derived From the Same Individuals With Schizophrenia,” published in the November 2023 issue of Psychiatry by Sawada et al.
Schizophrenia is a brain disorder with complex genetic and environmental causes, and studies on its cellular and molecular mechanisms in humans are limited despite decades of evidence of altered striatal function.
Researchers started a retrospective study to develop a method for differentiating induced pluripotent stem cells (iPSCs) into ventral forebrain organoids (VFOs) to explore neurodevelopmental alterations in the striatum associated with schizophrenia.
They created VFOs using iPSCs derived from postmortem dural fibroblasts of four individuals with schizophrenia and four neurotypical control individuals. The BrainSeq neurogenomics consortium had previously profiled postmortem caudate genotypes and transcriptomic data for these individuals. The selection of individuals ensured that the two groups had distinct schizophrenia polygenic risk scores (PRSs).
The results showed distinct developmental trajectories in inhibitory neuronal cells of schizophrenia individuals versus controls in VFOs using single-cell RNA sequencing. Notably, patients’ inhibitory neurons exhibited accelerated maturation. Additionally, genes upregulated in schizophrenia VFOs’ inhibitory neurons significantly overlapped with upregulated genes in postmortem caudate tissue of individuals with schizophrenia compared to controls, which included the iPSC cohort’s donors.
Investigators concluded that striatal neurons from high-PRS individuals with schizophrenia show early brain development abnormalities in VFOs.
Source: ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.20220723
