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Induction of dopaminergic neurons for neuronal subtype-specific modeling of psychiatric disease risk

Molecular Psychiatry volume 28, pages 1970–1982 (2023)Cite this article

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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 and electrophysiological properties consistent with midbrain dopaminergic neuron identity, such as slow-rising after- hyperpolarization potentials, an action potential duration of ~3 ms, tonic sub-threshold oscillatory activity, and spontaneous burst firing at a 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, as well as those from isogenic induced GABAergic and glutamatergic neurons, were enriched in loci conferring heritability for cannabis use disorder, schizophrenia, and bipolar disorder; however, each neuronal subtype demonstrated subtype-specific heritability enrichments in biologically relevant pathways, and iDANs alone were uniquely enriched in autism spectrum disorder risk loci. Therefore, iDANs provide a critical tool for modeling midbrain dopaminergic neuron development and dysfunction in psychiatric disease.

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Fig. 1: Production of induced dopaminergic neurons with ASCL1, LMX1B, and NURR1 transduction.
Fig. 2: Marker gene expression, purity, and dopamine production in iDANs.
Fig. 3: Electrophysiological characterization of iDANs.
Fig. 4: Transcriptomic analysis of iDANs.
Fig. 5: Neuronal subtype heritability enrichment for psychiatric disorders among hiPSC-derived neurons.
Fig. 6: Biological interpretation of iDAN-specific gene expression with differential enrichment in genetic loci associated with schizophrenia (SCZ), bipolar disorder (BIP), autism spectrum disorder (ASD), and cannabis use disorder (CUD).

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Data availability

The source data described in this manuscript are available via the PsychENCODE Knowledge Portal (https://psychencode.synapse.org/). The PsychENCODE Knowledge Portal is a platform for accessing data, analyses, and tools generated through grants funded by the National Institute of Mental Health (NIMH) PsychENCODE program. Data is available for general research use according to the following requirements for data access and data attribution: (https://psychencode.synapse.org/DataAccess). For access to content described in this manuscript see: https://doi.org/10.7303/syn25500352.

Code availability

Available from the authors upon request.

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Acknowledgements

This research was supported by R01MH106056, U01DA047880, R01DA048279, and 6R56MH101454. Figures in this manuscript were created with Biorender.com. The authors wish to thank Rachel Oren for helpful feedback on an earlier version of this manuscript, Dana Infante for assistance in sample collection, and Dr. Stefano Marenco, Dr. Barbara Lipska, and Dr. Pavan Auluck and their staff in the Human Brain Collection Core at the National Institutes of Health for providing postmortem brain tissues.

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Authors and Affiliations

  1. Pamela 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, USA

    Samuel K. Powell, Callan O’Shea, Kayla Townsley, Iya Prytkova, Kristina Dobrindt, Rahat Elahi, Marina Iskhakova, Tova Lambert, Aditi Valada, Seok-Man Ho, Laura M. Huckins, Schahram Akbarian & Kristen J. Brennand

  2. Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Samuel K. Powell, Callan O’Shea, Kayla Townsley, Iya Prytkova, Kristina Dobrindt, Rahat Elahi, Marina Iskhakova, Tova Lambert, Aditi Valada, Seok-Man Ho, Paul A. Slesinger, Schahram Akbarian & Kristen J. Brennand

  3. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Samuel K. Powell, Callan O’Shea, Kayla Townsley, Kristina Dobrindt, Rahat Elahi, Marina Iskhakova, Tova Lambert, Aditi Valada, Seok-Man Ho, Laura M. Huckins, Schahram Akbarian & Kristen J. Brennand

  4. Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Samuel K. Powell, Callan O’Shea, Kayla Townsley, Kristina Dobrindt, Rahat Elahi, Seok-Man Ho & Kristen J. Brennand

  5. Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Samuel K. Powell, Kayla Townsley & Iya Prytkova

  6. Division of Molecular Psychiatry, Department of Psychiatry, Yale University, New Haven, CT, USA

    Samuel K. Powell, Callan O’Shea, Kristina Dobrindt & Kristen J. Brennand

  7. New York Genome Center, New York, NY, USA

    Will Liao

Authors
  1. Samuel K. Powell
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  2. Callan O’Shea
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  3. Kayla Townsley
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  4. Iya Prytkova
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  5. Kristina Dobrindt
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  6. Rahat Elahi
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  7. Marina Iskhakova
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  8. Tova Lambert
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  9. Aditi Valada
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  10. Will Liao
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  11. Seok-Man Ho
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  12. Paul A. Slesinger
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  13. Laura M. Huckins
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  14. Schahram Akbarian
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  15. Kristen J. Brennand
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Contributions

SKP, SA, and KJB conceived of the study. SKP, KT, IP, KD, PS, LMH, SA, and KJP designed experiments. SKP, COS, IP, KD, RE, and SH conducted experiments. MI, TL, and AV performed FANS of post-mortem samples. SKP, COS, MI, TL, and AV prepared RNA-sequencing libraries. SKP, KT, and WL conducted computational and bioinformatic analyses. SKP wrote the paper, with contributions from KT and KD. All authors reviewed the manuscript and approved of it in its final form.

Corresponding authors

Correspondence to Schahram Akbarian or Kristen J. Brennand.

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The authors declare no competing interests.

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Powell, S.K., O’Shea, C., Townsley, K. et al. Induction of dopaminergic neurons for neuronal subtype-specific modeling of psychiatric disease risk. Mol Psychiatry 28, 1970–1982 (2023). https://doi.org/10.1038/s41380-021-01273-0

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  • DOI: https://doi.org/10.1038/s41380-021-01273-0

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