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Mol Psychiatry. 2016 Jan;21(1):62-70. doi: 10.1038/mp.2015.101. Epub 2015 Jul 28.

Direct conversion of human fibroblasts to induced serotonergic neurons.

Xu Z1,2,3, Jiang H2,3, Zhong P2,3, Yan Z2,3, Chen S1, Feng J2,3.

Author information

1
Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2
Veterans Affairs Western New York Healthcare System, Buffalo, NY, USA.
3
Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY, USA.

Abstract

Serotonergic (5HT) neurons exert diverse and widespread functions in the brain. Dysfunction of the serotonergic system gives rise to a variety of mental illnesses including depression, anxiety, obsessive compulsive disorder, autism and eating disorders. Here we show that human primary fibroblasts were directly converted to induced serotonergic (i5HT) neurons by the expression of Ascl1, Foxa2, Lmx1b and FEV. The transdifferentiation was enhanced by p53 knockdown and appropriate culture conditions including hypoxia. The i5HT neurons expressed markers for mature serotonergic neurons, had Ca(2+)-dependent 5HT release and selective 5HT uptake, exhibited spontaneous action potentials and spontaneous excitatory postsynaptic currents. Application of serotonin significantly increased the firing rate of spontaneous action potentials, demonstrating the functional utility of i5HT neurons for studying serotonergic neurotransmission. The availability of human i5HT neurons will be very useful for research and drug discovery on many serotonin-related mental disorders.

PMID:
26216300
PMCID:
PMC4518549
DOI:
10.1038/mp.2015.101
[Indexed for MEDLINE]
Free PMC Article

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