RT Journal Article SR Electronic T1 Induction of Dopaminergic Neurons for Neuronal Subtype-Specific Modeling of Psychiatric Disease Risk JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.04.01.438094 DO 10.1101/2021.04.01.438094 A1 Powell, Samuel K. A1 O’Shea, Callan A1 Townsley, Kayla A1 Prytkova, Iya A1 Dobrindt, Kristina A1 Elahi, Rahat A1 Iskhakova, Marina A1 Lambert, Tova A1 Valada, Aditi A1 Liao, Will A1 Ho, Seok-Man A1 Slesinger, Paul A. A1 Huckins, Laura M. A1 Akbarian, Schahram A1 Brennand, Kristen J. YR 2021 UL http://biorxiv.org/content/early/2021/04/02/2021.04.01.438094.abstract AB 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 StatementThe authors have declared no competing interest.