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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8898985/ https://www.ncbi.nlm.nih.gov/pubmed/34493831 http://dx.doi.org/10.1038/s41380-021-01273-0 |
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author | Powell, Samuel K. O’Shea, Callan Townsley, Kayla Prytkova, Iya Dobrindt, Kristina Elahi, Rahat Iskhakova, Marina Lambert, Tova Valada, Aditi Liao, Will Ho, Seok-Man Slesinger, Paul A. Huckins, Laura M. Akbarian, Schahram Brennand, Kristen J. |
author_facet | Powell, Samuel K. O’Shea, Callan Townsley, Kayla Prytkova, Iya Dobrindt, Kristina Elahi, Rahat Iskhakova, Marina Lambert, Tova Valada, Aditi Liao, Will Ho, Seok-Man Slesinger, Paul A. Huckins, Laura M. Akbarian, Schahram Brennand, Kristen J. |
author_sort | Powell, Samuel K. |
collection | PubMed |
description | 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 ~3ms, 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. |
format | Online Article Text |
id | pubmed-8898985 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
record_format | MEDLINE/PubMed |
spelling | pubmed-88989852023-03-07 Induction of Dopaminergic Neurons for Neuronal Subtype-Specific Modeling of Psychiatric Disease Risk Powell, Samuel K. O’Shea, Callan Townsley, Kayla Prytkova, Iya Dobrindt, Kristina Elahi, Rahat Iskhakova, Marina Lambert, Tova Valada, Aditi Liao, Will Ho, Seok-Man Slesinger, Paul A. Huckins, Laura M. Akbarian, Schahram Brennand, Kristen J. Mol Psychiatry Article 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 ~3ms, 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. 2023-05 2021-09-07 /pmc/articles/PMC8898985/ /pubmed/34493831 http://dx.doi.org/10.1038/s41380-021-01273-0 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: https://www.springernature.com/gp/open-research/policies/accepted-manuscript-terms |
spellingShingle | Article Powell, Samuel K. O’Shea, Callan Townsley, Kayla Prytkova, Iya Dobrindt, Kristina Elahi, Rahat Iskhakova, Marina Lambert, Tova Valada, Aditi Liao, Will Ho, Seok-Man Slesinger, Paul A. Huckins, Laura M. Akbarian, Schahram Brennand, Kristen J. Induction of Dopaminergic Neurons for Neuronal Subtype-Specific Modeling of Psychiatric Disease Risk |
title | Induction of Dopaminergic Neurons for Neuronal Subtype-Specific Modeling of Psychiatric Disease Risk |
title_full | Induction of Dopaminergic Neurons for Neuronal Subtype-Specific Modeling of Psychiatric Disease Risk |
title_fullStr | Induction of Dopaminergic Neurons for Neuronal Subtype-Specific Modeling of Psychiatric Disease Risk |
title_full_unstemmed | Induction of Dopaminergic Neurons for Neuronal Subtype-Specific Modeling of Psychiatric Disease Risk |
title_short | Induction of Dopaminergic Neurons for Neuronal Subtype-Specific Modeling of Psychiatric Disease Risk |
title_sort | induction of dopaminergic neurons for neuronal subtype-specific modeling of psychiatric disease risk |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8898985/ https://www.ncbi.nlm.nih.gov/pubmed/34493831 http://dx.doi.org/10.1038/s41380-021-01273-0 |
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