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.