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Simone Mayer1, Jiadong Chen1, Dmitry Velmeshev1

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Summary
This summary is machine-generated.

Neurotransmitter signaling in the developing human brain is cell-type-specific. Calcium responses reveal physiological diversity in neural progenitor cells, with serotonin receptor HTR2A uniquely activating human radial glia.

Keywords:
calcium imagingdifferentiationhuman neocortical developmentintermediate progenitor cellsneurogenesisneurotransmitterradial gliaradial glia scaffoldserotoninsingle-cell RNA sequencing

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Area of Science:

  • Developmental Neuroscience
  • Cellular Physiology
  • Neurobiology

Background:

  • The developing human neocortex features diverse progenitor cells generating various cell types.
  • Progenitor cells and nascent neurons are known to respond to neurotransmitter signaling cues.
  • While single-cell RNA sequencing identifies cellular diversity, physiological heterogeneity remains uncharacterized.

Purpose of the Study:

  • To map physiological heterogeneity, specifically intracellular calcium (Ca2+) responses, onto developing human neocortical cell types.
  • To investigate the dynamic changes in Ca2+ responses during neural lineage progression.
  • To explore the role of specific neurotransmitter signaling, such as serotonin receptor HTR2A, in human neocortical development.

Main Methods:

  • Combined intracellular Ca2+ measurements with neurotransmitter receptor agonists and single-cell RNA sequencing on the same cells.
  • Analyzed Ca2+ elevation dynamics and correlated them with molecular cell identity.
  • Investigated the function of the serotonin receptor HTR2A in human radial glia.

Main Results:

  • Calcium (Ca2+) responses to neurotransmitters are cell-type-specific and dynamically change with lineage progression in the developing neocortex.
  • Physiological response properties predict molecular cell identity and reveal diversity beyond transcriptomic data.
  • The serotonin receptor HTR2A selectively activates human radial glia, and its inhibition disrupts the radial glial scaffold, a mechanism not observed in mice.

Conclusions:

  • Neurotransmitter signaling is highly specific in the developing human neocortex, contributing to cellular and physiological diversity.
  • Physiological measurements provide a complementary layer of cell-type identification and reveal novel aspects of neural development.
  • Evolutionarily divergent mechanisms of physiological signaling exist, as exemplified by the distinct role of HTR2A in human versus mouse radial glia.