Serotonergic neuron regulation informed by in vivo single-cell transcriptomics

FASEB J. 2014 Feb;28(2):771-80. doi: 10.1096/fj.13-240267. Epub 2013 Nov 5.


Despite the recognized importance of the dorsal raphe (DR) serotonergic (5-HT) nuclei in the pathophysiology of depression and anxiety, the molecular components/putative drug targets expressed by these neurons are poorly characterized. Utilizing the promoter of an ETS domain transcription factor that is a stable marker of 5-HT neurons (Pet-1) to drive 5-HT neuronal expression of YFP, we identified 5-HT neurons in live acute slices. We isolated RNA from single 5-HT neurons in the ventromedial and lateral wings of the DR and performed single-cell RNA-Seq analysis identifying >500 G-protein coupled receptors (GPCRs) including receptors for classical transmitters, lipid signals, and peptides as well as dozens of orphan-GPCRs. Using these data to inform our selection of receptors to assess, we found that oxytocin and lysophosphatidic acid 1 receptors are translated and active in costimulating, with the α1-adrenergic receptor, the firing of DR 5-HT neurons, while the effects of histamine are inhibitory and exerted at H3 histamine receptors. The inhibitory histamine response provides evidence for tonic in vivo histamine inhibition of 5-HT neurons. This study illustrates that unbiased single-cell transcriptomics coupled with functional analyses provides novel insights into how neurons and neuronal systems are regulated.

Keywords: GPCR; RNA-Seq; dorsal raphe; electophysiology; histamine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Electrophysiology
  • In Vitro Techniques
  • Male
  • Mice
  • Receptors, G-Protein-Coupled / metabolism
  • Serotonergic Neurons / metabolism*
  • Serotonin / metabolism


  • Receptors, G-Protein-Coupled
  • Serotonin