Altered resting-state functional connectivity in hiPSCs-derived neuronal networks from schizophrenia patients

Abstract

Schizophrenia (SZ) is a severe mental disorder that arises from abnormal neurodevelopment, caused by genetic and environmental factors. SZ often involves distortions in reality perception and it is widely associated with alterations in brain connectivity. In the present work, we used Human Induced Pluripotent Stem Cells (hiPSCs)-derived neuronal cultures to study neural communicational dynamics during early development in SZ. We conducted gene and protein expression profiling, calcium imaging recordings, and applied a mathematical model to quantify the dynamism of functional connectivity (FC) in hiPSCs-derived neuronal networks. Along the neurodifferentiation process, SZ networks displayed altered gene expression of the glutamate receptor-related proteins HOMER1 and GRIN1 compared to healthy control (HC) networks, suggesting a possible tendency to develop hyperexcitability. Resting-state FC in neuronal networks derived from HC and SZ patients emerged as a dynamic phenomenon exhibiting connectivity configurations reoccurring in time (hub states). Compared to HC, SZ networks were less thorough in exploring different FC configurations, changed configurations less often, presented a reduced repertoire of hub states and spent longer uninterrupted time intervals in this less diverse universe of hubs. Our results suggest that alterations in the communicational dynamics of SZ emerging neuronal networks might contribute to the previously described brain FC anomalies in SZ patients, by compromising the ability of their neuronal networks for rapid and efficient reorganization through different activity patterns.