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Recapitulation of Perturbed Striatal Gene Expression Dynamics of Donors' Brains With Ventral Forebrain Organoids Derived From the Same Individuals With Schizophrenia. | LitMetric
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D'Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D'Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
Published: June 2024
AI Article Synopsis
Article Abstract
Objective: Schizophrenia is a brain disorder that originates during neurodevelopment and has complex genetic and environmental etiologies. Despite decades of clinical evidence of altered striatal function in affected patients, studies examining its cellular and molecular mechanisms in humans are limited. To explore neurodevelopmental alterations in the striatum associated with schizophrenia, the authors established a method for the differentiation of induced pluripotent stem cells (iPSCs) into ventral forebrain organoids (VFOs).
Methods: VFOs were generated from postmortem dural fibroblast-derived iPSCs of four individuals with schizophrenia and four neurotypical control individuals for whom postmortem caudate genotypes and transcriptomic data were profiled in the BrainSeq neurogenomics consortium. Individuals were selected such that the two groups had nonoverlapping schizophrenia polygenic risk scores (PRSs).
Results: Single-cell RNA sequencing analyses of VFOs revealed differences in developmental trajectory between schizophrenia and control individuals in which inhibitory neuronal cells from the patients exhibited accelerated maturation. Furthermore, upregulated genes in inhibitory neurons in schizophrenia VFOs showed a significant overlap with upregulated genes in postmortem caudate tissue of individuals with schizophrenia compared with control individuals, including the donors of the iPSC cohort.
Conclusions: The findings suggest that striatal neurons derived from high-PRS individuals with schizophrenia carry abnormalities that originated during early brain development and that the VFO model can recapitulate disease-relevant cell type-specific neurodevelopmental phenotypes in a dish.
