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; 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

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, Olivia R. Soudry, Dwight Dickinson, Karen F. Berman, Jose A. Apud, Daniel R. WeinbergerKeri Martinowich, Andrew E. Jaffe, Richard E. Straub, Brady J. Maher

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	e2109395119
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	119
Issue number	3
DOIs	https://doi.org/10.1073/pnas.2109395119
State	Published - Jan 18 2022

Keywords

Electrophysiology
Schizophrenia
Sodium channel
Stem cell

ASJC Scopus subject areas

General

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10.1073/pnas.2109395119

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Page, S. C., Sripathy, S. R., Farinelli, F., Ye, Z., Wang, Y., Hiler, D. J., Pattie, E. A., Nguyen, C. V., Tippani, M., Moses, R. L., Chen, H. Y., Tran, M. N., Eagles, N. J., Stolz, J. M., Catallini, J. L., Soudry, O. R., Dickinson, D., Berman, K. F., Apud, J. A., ... Maher, B. J. (2022). Electrophysiological measures from human iPSC-derived neurons are associated with schizophrenia clinical status and predict individual cognitive performance. Proceedings of the National Academy of Sciences of the United States of America, 119(3), Article e2109395119. https://doi.org/10.1073/pnas.2109395119

Electrophysiological measures from human iPSC-derived neurons are associated with schizophrenia clinical status and predict individual cognitive performance. / Page, Stephanie Cerceo; Sripathy, Srinidhi Rao; Farinelli, Federica et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 119, No. 3, e2109395119, 18.01.2022.

Research output: Contribution to journal › Article › peer-review

Page, SC, Sripathy, SR, Farinelli, F, Ye, Z, Wang, Y, Hiler, DJ, Pattie, EA, Nguyen, CV, Tippani, M, Moses, RL, Chen, HY, Tran, MN, Eagles, NJ, Stolz, JM, Catallini, JL, Soudry, OR, Dickinson, D, Berman, KF, Apud, JA, Weinberger, DR, Martinowich, K, Jaffe, AE, Straub, RE & Maher, BJ 2022, 'Electrophysiological measures from human iPSC-derived neurons are associated with schizophrenia clinical status and predict individual cognitive performance', Proceedings of the National Academy of Sciences of the United States of America, vol. 119, no. 3, e2109395119. https://doi.org/10.1073/pnas.2109395119

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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.",

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AU - Page, Stephanie Cerceo

AU - Sripathy, Srinidhi Rao

AU - Farinelli, Federica

AU - Ye, Zengyou

AU - Wang, Yanhong

AU - Hiler, Daniel J.

AU - Pattie, Elizabeth A.

AU - Nguyen, Claudia V.

AU - Tippani, Madhavi

AU - Moses, Rebecca L.

AU - Chen, Huei Ying

AU - Tran, Matthew Nguyen

AU - Eagles, Nicholas J.

AU - Stolz, Joshua M.

AU - Catallini, Joseph L.

AU - Soudry, Olivia R.

AU - Dickinson, Dwight

AU - Berman, Karen F.

AU - Apud, Jose A.

AU - Weinberger, Daniel R.

AU - Martinowich, Keri

AU - Jaffe, Andrew E.

AU - Straub, Richard E.

AU - Maher, Brady J.

N1 - Publisher Copyright: © This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

PY - 2022/1/18

Y1 - 2022/1/18

N2 - 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.

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KW - Sodium channel

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

Abstract

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