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.
authors.affiliation: Salk Institute for Biological Studies, Stanford Consortium for Regenerative Medicine, La Jolla, CA, USA.|SAHMRI Mind & Brain, Laboratory for Human Neurophysiology and Genetics, School of Medicine Flinders University, Adelaide, SA, Australia.
authors.forename: C
authors.identifier: 0000-0001-8321-0852
authors.initials: C
authors.lastname: Bardy
authors.affiliation: Salk Institute for Biological Studies, Stanford Consortium for Regenerative Medicine, La Jolla, CA, USA.|Division of Translational Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van den Hurk
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Kakaradov
authors.affiliation: Salk Institute for Biological Studies, Stanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Erwin
authors.affiliation: Salk Institute for Biological Studies, Stanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
authors.forename: B N
authors.initials: BN
authors.lastname: Jaeger
authors.affiliation: Salk Institute for Biological Studies, Stanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
authors.forename: R V
authors.initials: RV
authors.lastname: Hernandez
authors.affiliation: Salk Institute for Biological Studies, Stanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Eames
authors.affiliation: Salk Institute for Biological Studies, Stanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Paucar
authors.affiliation: Salk Institute for Biological Studies, Stanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Gorris
authors.affiliation: Salk Institute for Biological Studies, Stanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Marchand
authors.affiliation: Salk Institute for Biological Studies, Stanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Jappelli
authors.affiliation: Salk Institute for Biological Studies, Stanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Barron
authors.affiliation: Salk Institute for Biological Studies, Stanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Bryant
authors.affiliation: Salk Institute for Biological Studies, Stanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kellogg
authors.affiliation: J. Craig Venter Institute, La Jolla, CA, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Lasken
authors.affiliation: Division of Translational Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands.
authors.forename: B P F
authors.initials: BP
authors.lastname: Rutten
authors.affiliation: Division of Translational Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands.
authors.forename: H W M
authors.initials: HW
authors.lastname: Steinbusch
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore and Molecular Engineering Laboratory, A*STAR, Singapore, Singapore.
authors.forename: G W
authors.initials: GW
authors.lastname: Yeo
authors.affiliation: Salk Institute for Biological Studies, Stanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
authors.forename: F H
authors.initials: FH
authors.lastname: Gage
mesh_terms: D000200:Action Potentials / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004594:Electrophysiology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology; D000069550:Machine Learning; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D039904:Pluripotent Stem Cells; D012313:RNA; D017423:Sequence Analysis, RNA / Q000379:methods*; D059010:Single-Cell Analysis / Q000379:methods*
chemical_list: D012313:RNA