@article{bf28386ebf03479894b4c460d46108e4,
title = "Predicting the functional states of human iPSC-derived neurons with single-cell RNA-seq and electrophysiology",
abstract = "Human neural progenitors derived from pluripotent stem cells develop into electrophysiologically active neurons at heterogeneous rates, which can confound disease-relevant discoveries in neurology and psychiatry. By combining patch clamping, morphological and transcriptome analysis on single-human neurons in vitro, we defined a continuum of poor to highly functional electrophysiological states of differentiated neurons. The strong correlations between action potentials, synaptic activity, dendritic complexity and gene expression highlight the importance of methods for isolating functionally comparable neurons for in vitro investigations of brain disorders. Although whole-cell electrophysiology is the gold standard for functional evaluation, it often lacks the scalability required for disease modeling studies. Here, we demonstrate a multimodal machine-learning strategy to identify new molecular features that predict the physiological states of single neurons, independently of the time spent in vitro. As further proof of concept, we selected one of the potential neurophysiological biomarkers identified in this study - GDAP1L1 - to isolate highly functional live human neurons in vitro.",
author = "C. Bardy and {Van Den Hurk}, M. and B. Kakaradov and Erwin, {J. A.} and Jaeger, {B. N.} and Hernandez, {R. V.} and T. Eames and Paucar, {A. A.} and M. Gorris and C. Marchand and R. Jappelli and J. Barron and Bryant, {A. K.} and M. Kellogg and Lasken, {R. S.} and Rutten, {B. P.F.} and Steinbusch, {H. W.M.} and Yeo, {G. W.} and Gage, {F. H.}",
note = "Funding Information: We are grateful to Elisabeth Santo and Sarah Marshall for help with the morphological reconstruction. We thank Gage lab members Bobbie Miller and Lynne Moore for preparation of viral vectors and Eunice Meija for immunohistochemistry. Thanks to Gage lab (Prattap Venepalli, Apua Paquola, Sara Linker, Son Pham) and Yeo lab (Olga Botvinnik) members for fruitful bioinformatics discussions on single-cell transcriptomics. We thank Mary Lynn Gage for edits on the manuscript. This study was supported by grants from Ipsen Pharma, Annette C. Merle-Smith, The Leona M. and Harry B. Helmsley Charitable Trust Grant #2012-PG-MED002, Bob and Mary Jane Engman, the JPB Foundation, G Harold and Leila Y. Mathers Foundation, and NIH Grants MH095741 (to F.H.G.); also by a Fay/Frank Seed Grant from the Brain Research Foundation and NIH Grants NS075449, HG004659, HG007005 (to G.W.Y.). G.W.Y. is an Alfred P Sloan Research Fellow. This work was also supported by NSF Graduate Research Fellowship (to B.K.), the George E. Hewitt Foundation for Medical Research (to J.E.) the EMBO Long-term fellowship, the Bettencourt Schueller Foundation and the Philippe Foundation (B.N.J.) and the FP7 Marie Curie International Outgoing Fellowship for Career Development (to C.B.). Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.",
year = "2016",
month = nov,
day = "1",
doi = "10.1038/mp.2016.158",
language = "English (US)",
volume = "21",
pages = "1573--1588",
journal = "Molecular psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "11",
}