标题：Electrophysiological measures from human iPSC-derived neurons are associated with schizophrenia clinical status and predict individual cognitive performance
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：3
DOI：10.1073/pnas.2109395119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Schizophrenia (SCZ) is a complex, highly heritable, neurodevelopmental disorder with marked clinical heterogeneity and no clear pathological mechanism or cellular pathology. The polygenic nature of the disorder has hindered our ability to model the disorder in the laboratory. Prior studies of cortical neurons differentiated from SCZ patient and control hiPSCs have identified interesting differences but their relevance to clinical illness in adults remains unclear. We now identify electrophysiological measures that associate with diagnosis and/or predict the severity of clinical and cognitive features of individual adult donors. These results demonstrate neurophysiological measures that are related to the patient’s personal clinical characteristics, which may help with patient stratification and the development of novel biomarkers and therapeutic targets.
Neurons derived from human induced pluripotent stem cells (hiPSCs) have been used to model basic cellular aspects of neuropsychiatric disorders, but the relationship between the emergent phenotypes and the clinical characteristics of donor individuals has been unclear. We analyzed RNA expression and indices of cellular function in hiPSC-derived neural progenitors and cortical neurons generated from 13 individuals with high polygenic risk scores (PRSs) for schizophrenia (SCZ) and a clinical diagnosis of SCZ, along with 15 neurotypical individuals with low PRS. We identified electrophysiological measures in the patient-derived neurons that implicated altered Na
+ channel function, action potential interspike interval, and gamma-aminobutyric acid–ergic neurotransmission. Importantly, electrophysiological measures predicted cardinal clinical and cognitive features found in these SCZ patients. The identification of basic neuronal physiological properties related to core clinical characteristics of illness is a potentially critical step in generating leads for novel therapeutics.
