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Nitric oxide negatively regulates mammalian adult neurogenesis.

Neural progenitor cells are widespread throughout the adult central nervous system but only give rise to neurons in specific loci. Negative regulators of neurogenesis have therefore been postulated, but none have yet been identified as subserving a significant role in the adult brain. Here we report that nitric oxide (NO) acts as an important negative regulator of cell proliferation in the adult mammalian brain. We used two independent approaches to examine the function of NO in adult neurogenesis. In a pharmacological approach, we suppressed NO production in the rat brain by intraventricular infusion of an NO synthase inhibitor. In a genetic approach, we generated a null mutant neuronal NO synthase knockout mouse line by targeting the exon encoding active center of the enzyme. In both models, the number of new cells generated in neurogenic areas of the adult brain, the olfactory subependyma and the dentate gyrus, was strongly augmented, which indicates that division of neural stem cells in the adult brain is controlled by NO and suggests a strategy for enhancing neurogenesis in the adult central nervous system.

Pubmed ID: 12886012


  • Packer MA
  • Stasiv Y
  • Benraiss A
  • Chmielnicki E
  • Grinberg A
  • Westphal H
  • Goldman SA
  • Enikolopov G


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

August 5, 2003

Associated Grants


Mesh Terms

  • Animals
  • Brain
  • Bromodeoxyuridine
  • Cell Division
  • Central Nervous System
  • Exons
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Models, Genetic
  • Molecular Sequence Data
  • NG-Nitroarginine Methyl Ester
  • Neurons
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Open Reading Frames
  • Rats
  • Recombination, Genetic