Age-dependent Dystonia in Striatal Gγ7 Deficient Mice Is Reversed by the Dopamine D2 Receptor Agonist Pramipexole

J Neurochem. 2013 Mar;124(6):844-54. doi: 10.1111/jnc.12149. Epub 2013 Feb 19.

Abstract

Gγ7 is enriched in striatum and forms a heterotrimeric complex with Gαolf /Gβ, which is coupled to D1 receptor (D1R). Here, we attempted to characterize the pathophysiological, neurochemical, and pharmacological features of mice deficient of Gγ7 gene. Gγ7 knockout mice exhibited age-dependent deficiency in rotarod behavior and increased dystonia-like clasping reflex without loss of striatal neurons. The neurochemical basis for the motor manifestations using immunoblot analysis revealed increased levels of D1R, ChAT and NMDA receptor subunits (NR1 and NR2B) concurrent with decreased levels of D2R and Gαolf , possibly because of the secondary changes of decreased Gαolf /Gγ7-mediated D1R transmission. These behavioral and neurochemical changes are closely related to those observed in Huntington's disease (HD) human subjects and HD model mice. Taking advantage of the finding of D2R down-regulation in Gγ7 knockout mice and the dopamine-mediated synergistic relationship in the control of locomotion between D2R-striatopallidal and D1R-stritonigral neurons, we hypothesized that D2-agonist pramipexole would reverse behavioral dyskinesia caused by defective D1R/Gαolf signaling. Indeed, the rotarod deficiency and clasping reflex were reversed by pramipexole treatment under chronic administration. These findings suggest that Gγ7 knockout mice could be a new type of movement disorders, including HD and useful for the evaluation of therapeutic candidates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Benzothiazoles / pharmacology
  • Benzothiazoles / therapeutic use*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Dopamine Agonists / pharmacology
  • Dopamine Agonists / therapeutic use*
  • Dystonia / drug therapy*
  • Dystonia / metabolism*
  • GTP-Binding Protein gamma Subunits / deficiency*
  • Male
  • Mice
  • Mice, Knockout
  • Pramipexole
  • Receptors, Dopamine D2 / agonists*
  • Receptors, Dopamine D2 / physiology

Substances

  • Benzothiazoles
  • Dopamine Agonists
  • G protein gamma 7 protein, human
  • GTP-Binding Protein gamma Subunits
  • Receptors, Dopamine D2
  • Pramipexole