Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision

Nature. 2012 Sep 6;489(7414):150-4. doi: 10.1038/nature11306.

Abstract

Adult neurogenesis arises from neural stem cells within specialized niches. Neuronal activity and experience, presumably acting on this local niche, regulate multiple stages of adult neurogenesis, from neural progenitor proliferation to new neuron maturation, synaptic integration and survival. It is unknown whether local neuronal circuitry has a direct impact on adult neural stem cells. Here we show that, in the adult mouse hippocampus, nestin-expressing radial glia-like quiescent neural stem cells (RGLs) respond tonically to the neurotransmitter γ-aminobutyric acid (GABA) by means of γ2-subunit-containing GABAA receptors. Clonal analysis of individual RGLs revealed a rapid exit from quiescence and enhanced symmetrical self-renewal after conditional deletion of γ2. RGLs are in close proximity to terminals expressing 67-kDa glutamic acid decarboxylase (GAD67) of parvalbumin-expressing (PV+) interneurons and respond tonically to GABA released from these neurons. Functionally, optogenetic control of the activity of dentate PV+ interneurons, but not that of somatostatin-expressing or vasoactive intestinal polypeptide (VIP)-expressing interneurons, can dictate the RGL choice between quiescence and activation. Furthermore, PV+ interneuron activation restores RGL quiescence after social isolation, an experience that induces RGL activation and symmetrical division. Our study identifies a niche cell–signal–receptor trio and a local circuitry mechanism that control the activation and self-renewal mode of quiescent adult neural stem cells in response to neuronal activity and experience.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Lineage* / drug effects
  • Cell Proliferation / drug effects
  • Dentate Gyrus / cytology
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / metabolism
  • Female
  • GABA Modulators / pharmacology
  • GABA-A Receptor Agonists / pharmacology
  • GABA-A Receptor Antagonists / pharmacology
  • Interneurons / cytology
  • Interneurons / drug effects
  • Interneurons / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neural Pathways / drug effects
  • Neural Pathways / physiology*
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Neurogenesis* / drug effects
  • Neuroglia / cytology
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Parvalbumins / metabolism
  • Receptors, GABA-A / metabolism
  • Signal Transduction / drug effects
  • Somatostatin / metabolism
  • Stem Cell Niche / drug effects
  • Stem Cell Niche / physiology
  • Vasoactive Intestinal Peptide / metabolism
  • gamma-Aminobutyric Acid / metabolism

Substances

  • GABA Modulators
  • GABA-A Receptor Agonists
  • GABA-A Receptor Antagonists
  • Parvalbumins
  • Receptors, GABA-A
  • Vasoactive Intestinal Peptide
  • Somatostatin
  • gamma-Aminobutyric Acid