Publications

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

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.

Mol Psychiatry. 2021 Sep 7. doi: 10.1038/s41380-021-01273-0.

Authors

Other Contributors

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

 

  • 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.
  • 2Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 5Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 6Division of Molecular Psychiatry, Department of Psychiatry, Yale University, New Haven, CT, USA.
  • 7New York Genome Center, New York, NY, USA.
  • 8Pamela 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.
  • 9Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 10Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 11Pamela 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.
  • 12Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 13Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 14Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 15Division of Molecular Psychiatry, Department of Psychiatry, Yale University, New Haven, CT, USA.

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