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Induction of Dopaminergic Neurons for Neuronal Subtype-Specific Modeling of Psychiatric Disease Risk

View ORCID ProfileSamuel K. Powell, View ORCID ProfileCallan O’Shea, View ORCID ProfileKayla Townsley, View ORCID ProfileIya Prytkova, View ORCID ProfileKristina Dobrindt, Rahat Elahi, Marina Iskhakova, Tova Lambert, Aditi Valada, View ORCID ProfileWill Liao, Seok-Man Ho, Paul A. Slesinger, View ORCID ProfileLaura M. Huckins, Schahram Akbarian, View ORCID ProfileKristen J. Brennand
doi: https://doi.org/10.1101/2021.04.01.438094
Samuel K. Powell
1Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
2Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029
4Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
5Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029
6Division of Molecular Psychiatry, Department of Psychiatry, Yale University, New Haven CT, 06511
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  • ORCID record for Samuel K. Powell
Callan O’Shea
1Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
2Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029
4Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
6Division of Molecular Psychiatry, Department of Psychiatry, Yale University, New Haven CT, 06511
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Kayla Townsley
1Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
2Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029
4Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
5Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Iya Prytkova
1Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
2Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
5Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Kristina Dobrindt
1Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
2Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029
4Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
6Division of Molecular Psychiatry, Department of Psychiatry, Yale University, New Haven CT, 06511
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Rahat Elahi
1Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
2Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029
4Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Marina Iskhakova
1Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
2Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Tova Lambert
1Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
2Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Aditi Valada
1Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
2Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Will Liao
7New York Genome Center, New York, NY, 10029
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  • ORCID record for Will Liao
Seok-Man Ho
1Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
2Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029
4Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Paul A. Slesinger
2Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Laura M. Huckins
1Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Schahram Akbarian
1Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
2Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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  • For correspondence: kristen.brennand@mssm.edu schahram.akbarian@mssm.edu
Kristen J. Brennand
1Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
2Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029
4Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
6Division of Molecular Psychiatry, Department of Psychiatry, Yale University, New Haven CT, 06511
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  • For correspondence: kristen.brennand@mssm.edu schahram.akbarian@mssm.edu
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ABSTRACT

Dopaminergic neurons are critical to movement, mood, addiction, and stress. Current techniques for generating dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) yield heterogenous cell populations with variable purity and inconsistent reproducibility between donors, hiPSC clones, and experiments. Here, we report the rapid (5 weeks) and efficient (~90%) induction of induced dopaminergic neurons (iDANs) through transient overexpression of lineage-promoting transcription factors combined with stringent selection across five donors. We observe maturation-dependent increase in dopamine synthesis, together with electrophysiological properties consistent with midbrain dopaminergic neuron identity, such as slow-rising after hyperpolarization potentials, an action potential duration of ~3ms, tonic sub-threshold oscillatory activity, and spontaneous burst firing at frequency of ~1.0-1.75 Hz. Transcriptome analysis reveals robust expression of genes involved in fetal midbrain dopaminergic neuron identity. Specifically expressed genes in iDANs, relative to their isogenic glutamatergic and GABAergic counterparts, were linked to the genetic risk architecture of a broad range of psychiatric traits, with iDANs showing particularly strong enrichment in loci conferring heritability for cannabis use disorder, schizophrenia, and bipolar disorder. Therefore, iDANs provide a critical tool for modeling midbrain dopaminergic neuron development and dysfunction in psychiatric disease.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • CONFLICT OF INTEREST STATEMENT The authors report that they have no conflicts of interest to disclose.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Induction of Dopaminergic Neurons for Neuronal Subtype-Specific Modeling of Psychiatric Disease Risk
Samuel K. Powell, Callan O’Shea, Kayla Townsley, Iya Prytkova, Kristina Dobrindt, Rahat Elahi, Marina Iskhakova, Tova Lambert, Aditi Valada, Will Liao, Seok-Man Ho, Paul A. Slesinger, Laura M. Huckins, Schahram Akbarian, Kristen J. Brennand
bioRxiv 2021.04.01.438094; doi: https://doi.org/10.1101/2021.04.01.438094
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Induction of Dopaminergic Neurons for Neuronal Subtype-Specific Modeling of Psychiatric Disease Risk
Samuel K. Powell, Callan O’Shea, Kayla Townsley, Iya Prytkova, Kristina Dobrindt, Rahat Elahi, Marina Iskhakova, Tova Lambert, Aditi Valada, Will Liao, Seok-Man Ho, Paul A. Slesinger, Laura M. Huckins, Schahram Akbarian, Kristen J. Brennand
bioRxiv 2021.04.01.438094; doi: https://doi.org/10.1101/2021.04.01.438094

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