Generation of functional human serotonergic neurons from fibroblasts

K. C. Vadodaria, J. Mertens, Apua Paquola, C. Bardy, X. Li, R. Jappelli, L. Fung, M. C. Marchetto, M. Hamm, M. Gorris, P. Koch, F. H. Gage

Research output: Contribution to journalArticle

Abstract

The brain's serotonergic system centrally regulates several physiological processes and its dysfunction has been implicated in the pathophysiology of several neuropsychiatric disorders. While in the past our understanding of serotonergic neurotransmission has come mainly from mouse models, the development of pluripotent stem cell and induced fibroblast-to-neuron (iN) transdifferentiation technologies has revolutionized our ability to generate human neurons in vitro. Utilizing these techniques and a novel lentiviral reporter for serotonergic neurons, we identified and overexpressed key transcription factors to successfully generate human serotonergic neurons. We found that overexpressing the transcription factors NKX2.2, FEV, GATA2 and LMX1B in combination with ASCL1 and NGN2 directly and efficiently generated serotonergic neurons from human fibroblasts. Induced serotonergic neurons (iSNs) showed increased expression of specific serotonergic genes that are known to be expressed in raphe nuclei. iSNs displayed spontaneous action potentials, released serotonin in vitro and functionally responded to selective serotonin reuptake inhibitors (SSRIs). Here, we demonstrate the efficient generation of functional human serotonergic neurons from human fibroblasts as a novel tool for studying human serotonergic neurotransmission in health and disease.

Original languageEnglish (US)
Pages (from-to)49-61
Number of pages13
JournalMolecular Psychiatry
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint

Serotonergic Neurons
Fibroblasts
Synaptic Transmission
Transcription Factors
Physiological Phenomena
Neurons
Induced Pluripotent Stem Cells
Raphe Nuclei
Serotonin Uptake Inhibitors
Action Potentials
Serotonin
Technology
Health
Brain
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Vadodaria, K. C., Mertens, J., Paquola, A., Bardy, C., Li, X., Jappelli, R., ... Gage, F. H. (2016). Generation of functional human serotonergic neurons from fibroblasts. Molecular Psychiatry, 21(1), 49-61. https://doi.org/10.1038/mp.2015.161

Generation of functional human serotonergic neurons from fibroblasts. / Vadodaria, K. C.; Mertens, J.; Paquola, Apua; Bardy, C.; Li, X.; Jappelli, R.; Fung, L.; Marchetto, M. C.; Hamm, M.; Gorris, M.; Koch, P.; Gage, F. H.

In: Molecular Psychiatry, Vol. 21, No. 1, 01.01.2016, p. 49-61.

Research output: Contribution to journalArticle

Vadodaria, KC, Mertens, J, Paquola, A, Bardy, C, Li, X, Jappelli, R, Fung, L, Marchetto, MC, Hamm, M, Gorris, M, Koch, P & Gage, FH 2016, 'Generation of functional human serotonergic neurons from fibroblasts', Molecular Psychiatry, vol. 21, no. 1, pp. 49-61. https://doi.org/10.1038/mp.2015.161
Vadodaria, K. C. ; Mertens, J. ; Paquola, Apua ; Bardy, C. ; Li, X. ; Jappelli, R. ; Fung, L. ; Marchetto, M. C. ; Hamm, M. ; Gorris, M. ; Koch, P. ; Gage, F. H. / Generation of functional human serotonergic neurons from fibroblasts. In: Molecular Psychiatry. 2016 ; Vol. 21, No. 1. pp. 49-61.
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