Local gene knockdown in the brain using viral-mediated RNA interference

Nat Med. 2003 Dec;9(12):1539-44. doi: 10.1038/nm964. Epub 2003 Nov 23.


Conditional mutant techniques that allow spatial and temporal control over gene expression can be used to create mice with restricted genetic modifications. These mice serve as powerful disease models in which gene function in adult tissues can be specifically dissected. Current strategies for conditional genetic manipulation are inefficient, however, and often lack sufficient spatial control. Here we use viral-mediated RNA interference (RNAi) to generate a specific knockdown of Th, the gene encoding the dopamine synthesis enzyme tyrosine hydroxylase, within midbrain neurons of adult mice. This localized gene knockdown resulted in behavioral changes, including a motor performance deficit and reduced response to a psychostimulant. These results underscore the potential of using viral-mediated RNAi for the rapid production and testing of new genetic disease models. Similar strategies may be used in other model species, and may ultimately find applications in human gene therapy.

MeSH terms

  • Animals
  • Base Sequence
  • Behavior, Animal
  • Brain / metabolism*
  • DNA / genetics
  • Dependovirus / genetics
  • Gene Expression
  • Gene Targeting / methods*
  • Genetic Vectors
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA Interference*
  • Tyrosine 3-Monooxygenase / biosynthesis
  • Tyrosine 3-Monooxygenase / genetics


  • DNA
  • Tyrosine 3-Monooxygenase