Electrophysiological measures from human iPSC-derived neurons are associated with schizophrenia clinical status and predict individual cognitive performance

Stephanie C. Page; Srinidhi Rao Sripathy; Federica Farinelli; Zengyou Ye; Yanhong Wang; Daniel J. Hiler; Elizabeth A. Pattie; Claudia V. Nguyen; Madhavi Tippani; Rebecca L. Moses; Huei-Ying Chen; Matthew Nguyen Tran; Nicholas J. Eagles; Joshua M. Stolz; Joseph L Catallini II; Olivia R. Soudry; Dwight Dickinson; Karen Faith Berman; Jose A. Apud; Daniel R. Weinberger; Keri Martinowich; Andrew E. Jaffe; Richard E. Straub; Brady J. Maher

doi:10.1073/pnas.2109395119

NeuroscienceProceedings of the National Academy of SciencesJan 11, 2022

Peer-reviewed journal article

Electrophysiological measures from human iPSC-derived neurons are associated with schizophrenia clinical status and predict individual cognitive performance

Stephanie C. Page iD, Srinidhi Rao Sripathy iD, Federica Farinelli iD, Zengyou Ye iD, Yanhong Wang iD, Daniel J. Hiler, Elizabeth A. Pattie iD, Claudia V. Nguyen iD, Madhavi Tippani iD, Rebecca L. Moses, Huei-Ying Chen iD, Matthew Nguyen Tran iD, Nicholas J. Eagles iD, Joshua M. Stolz, Joseph L Catallini II iD, Olivia R. Soudry, Dwight Dickinson iD, Karen Faith Berman iD, Jose A. Apud, Daniel R. Weinberger iD, Keri Martinowich iD, Andrew E. Jaffe iD, Richard E. Straub iD, Brady J. Maher iD

Abstract

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 (PRS) for schizophrenia and a clinical diagnosis of schizophrenia, along with 15 neurotypical individuals with low PRS. We identified electrophysiological measures associated with diagnosis that implicated altered Na+ channel function and GABA-ergic neurotransmission. Importantly, electrophysiological measures predicted cardinal clinical and cognitive features found in these schizophrenia 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.

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