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

Stephanie Cerceo 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 2nd; Olivia R Soudry; Dwight Dickinson; Karen F Berman; Jose A Apud; Daniel R Weinberger; Keri Martinowich; Andrew E Jaffe; Richard E Straub; Brady J Maher

doi:10.1073/pnas.2109395119

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

Proc Natl Acad Sci U S A. 2022 Jan 18;119(3):e2109395119. doi: 10.1073/pnas.2109395119.

Authors

Stephanie Cerceo Page¹, Srinidhi Rao Sripathy¹, Federica Farinelli¹, Zengyou Ye¹, Yanhong Wang¹, Daniel J Hiler¹, Elizabeth A Pattie¹, Claudia V Nguyen¹, Madhavi Tippani¹, Rebecca L Moses¹, Huei-Ying Chen¹, Matthew Nguyen Tran^{1

2}, Nicholas J Eagles¹, Joshua M Stolz¹, Joseph L Catallini 2nd^{1

3}, Olivia R Soudry¹, Dwight Dickinson⁴, Karen F Berman⁴, Jose A Apud⁴, Daniel R Weinberger^{1

2

5

6

7}, Keri Martinowich^{1

5

6}, Andrew E Jaffe^{1

3

5

6

8}, Richard E Straub¹, Brady J Maher^{9

5

6}

Affiliations

¹ Lieber Institute for Brain Development, Baltimore, MD 21205.
² McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205.
³ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205.
⁴ Clinical and Translational Neuroscience Branch, National Institute of Mental Health Intramural Research Program, NIH, Bethesda, MD 20892.
⁵ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205.
⁶ Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205.
⁷ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205.
⁸ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205.
⁹ Lieber Institute for Brain Development, Baltimore, MD 21205; brady.maher@libd.org.

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 (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.

Trial registration: ClinicalTrials.gov NCT00001486.

Keywords: electrophysiology; schizophrenia; sodium channel; stem cell.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Animals
Cell Line
Cellular Reprogramming
Cerebral Cortex / pathology
Cognition / physiology*
Electrophysiological Phenomena*
Humans
Induced Pluripotent Stem Cells / physiology*
Ion Channel Gating
Kinetics
Male
Neurons / physiology*
Phenotype
Rats
Schizophrenia / diagnosis
Schizophrenia / physiopathology*
Sodium Channels / metabolism

Substances

Sodium Channels

Associated data

ClinicalTrials.gov/NCT00001486