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Nat Biotechnol. 2016 Jan;34(1):89-94. doi: 10.1038/nbt.3435. Epub 2015 Dec 14.

Generation of serotonin neurons from human pluripotent stem cells.

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Waisman Center, University of Wisconsin, Madison, Wisconsin, USA.
School of Pharmacy, University of Wisconsin, Madison, Wisconsin, USA.
Department of Chemistry, University of Wisconsin, Madison, Wisconsin, USA.
Department of Neuroscience and Department of Neurology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.


Serotonin neurons located in the raphe nucleus of the hindbrain have crucial roles in regulating brain functions and have been implicated in various psychiatric disorders. Yet functional human serotonin neurons are not available for in vitro studies. Through manipulation of the WNT pathway, we demonstrate efficient differentiation of human pluripotent stem cells (hPSCs) to cells resembling central serotonin neurons, primarily those located in the rhombomeric segments 2-3 of the rostral raphe, which participate in high-order brain functions. The serotonin neurons express a series of molecules essential for serotonergic development, including tryptophan hydroxylase 2, exhibit typical electrophysiological properties and release serotonin in an activity-dependent manner. When treated with the FDA-approved drugs tramadol and escitalopram oxalate, they release or uptake serotonin in a dose- and time-dependent manner, suggesting the utility of these cells for the evaluation of drug candidates.

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