Abstract

Schizophrenia is a neurodevelopmental disorder associated with alterations in neuronal function and connectivity. It has been extensively modeled using neurons derived from induced pluripotent stem cells (iPSC), where significant differences between patients and healthy controls have been reported. Notably, spontaneous generation of astrocytes in these cultures can influence functional and molecular analyses. This study assesses whether schizophrenia (SZ) and healthy control (HC) iPSC-derived neuronal cultures significantly differ in their cellular composition and determines how these variations impact transcriptomic interpretations. iPSC from three HC and four SZ were differentiated into neuronal cultures and then characterized using immunostaining, RNA sequencing, transcriptomic deconvolution, and flow cytometry. Transcriptomic analysis identified differential gene expression in SZ cultures, enriched gene ontology (GO) pathways related to neurodevelopment and synaptic function. Additionally, SynGO analysis revealed altered expression of genes associated with pre- and postsynaptic compartments. Cell-type deconvolution showed enrichment of immature and postmitotic neuronal populations in SZ cultures, whereas HC cultures displayed higher astrocyte enrichment. The neuronal enrichment was further supported by flow cytometry, which indicated an increased proportion of NeuN-positive nuclei in SZ-derived cultures. Together, our results support a model where a shift in the neuronal–glial balance in schizophrenia neural cell populations may contribute to the disease-associated phenotypes.