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Mol Psychiatry. 2016 Nov;21(11):1573-1588. doi: 10.1038/mp.2016.158. Epub 2016 Oct 4.

Predicting the functional states of human iPSC-derived neurons with single-cell RNA-seq and electrophysiology.

Author information

1
Salk Institute for Biological Studies, Stanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
2
SAHMRI Mind & Brain, Laboratory for Human Neurophysiology and Genetics, School of Medicine Flinders University, Adelaide, SA, Australia.
3
Division of Translational Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands.
4
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
5
J. Craig Venter Institute, La Jolla, CA, USA.
6
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore and Molecular Engineering Laboratory, A*STAR, Singapore, Singapore.

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.

PMID:
27698428
PMCID:
PMC5071135
DOI:
10.1038/mp.2016.158
[Indexed for MEDLINE]
Free PMC Article

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