Neurotransmitter signaling regulates distinct phases of multimodal human interneuron migration

EMBO J. 2021 Dec 1;40(23):e108714. doi: 10.15252/embj.2021108714. Epub 2021 Oct 18.


Inhibitory GABAergic interneurons migrate over long distances from their extracortical origin into the developing cortex. In humans, this process is uniquely slow and prolonged, and it is unclear whether guidance cues unique to humans govern the various phases of this complex developmental process. Here, we use fused cerebral organoids to identify key roles of neurotransmitter signaling pathways in guiding the migratory behavior of human cortical interneurons. We use scRNAseq to reveal expression of GABA, glutamate, glycine, and serotonin receptors along distinct maturation trajectories across interneuron migration. We develop an image analysis software package, TrackPal, to simultaneously assess 48 parameters for entire migration tracks of individual cells. By chemical screening, we show that different modes of interneuron migration depend on distinct neurotransmitter signaling pathways, linking transcriptional maturation of interneurons with their migratory behavior. Altogether, our study provides a comprehensive quantitative analysis of human interneuron migration and its functional modulation by neurotransmitter signaling.

Keywords: cerebral organoid fusions; cortical interneuron migration; human brain development; live cell imaging; neurotransmitter signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Movement*
  • Cerebral Cortex / cytology
  • Cerebral Cortex / physiology*
  • HEK293 Cells
  • Humans
  • Interneurons / cytology
  • Interneurons / physiology*
  • Neurogenesis
  • Neurotransmitter Agents / metabolism*
  • Organoids / cytology
  • Organoids / physiology*
  • RNA-Seq
  • Single-Cell Analysis


  • Neurotransmitter Agents

Associated data

  • GEO/GSE161550
  • GEO/GSE182614