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Generation of functional human serotonergic neurons from fibroblasts

Molecular Psychiatry volume 21, pages 49–61 (2016)Cite this article

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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.

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Acknowledgements

KCV was supported by the Swiss National Science Foundation (SNSF) outgoing postdoctoral fellowship. JM and CB were supported by fellowships Glenn Center for Aging Research and the FP7 Marie Curie, respectively. This research was supported by Lynn and Edward Streim, the Robert and Mary Jane Engman Foundation, the JPB Foundation, and the Leona M and Harry B Helmsley Charitable Trust grant #2012-PG-MED002. We thank Dr Juergen Winkler for a line of primary human fibroblasts, Dr Manching Ku for help with RNA sequencing, Jamie Simon for help with illustrations, Dr Himanish Ghosh for help with semi-automated image analysis and Mary Lynn Gage for editorial comments.

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Author notes

  1. K C Vadodaria and J Mertens: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA

    K C Vadodaria, J Mertens, A Paquola, C Bardy, X Li, R Jappelli, L Fung, M C Marchetto, M Gorris & F H Gage

  2. University of California, San Diego (UCSD), La Jolla, CA, USA

    X Li & L Fung

  3. The Salk Institute for Biological Studies, La Jolla, CA, USA

    M Hamm

  4. Institute of Reconstructive Neurobiology, University of Bonn, Bonn,, Germany

    P Koch

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  1. K C Vadodaria
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Correspondence to F H Gage.

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Vadodaria, K., Mertens, J., Paquola, A. et al. Generation of functional human serotonergic neurons from fibroblasts. Mol Psychiatry 21, 49–61 (2016). https://doi.org/10.1038/mp.2015.161

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