Non-motor behavioural impairments in parkin-deficient mice

Eur J Neurosci. 2007 Oct;26(7):1902-11. doi: 10.1111/j.1460-9568.2007.05812.x. Epub 2007 Sep 20.

Abstract

Mutations in the parkin gene are the major cause of early-onset familial Parkinson's disease (PD). We previously reported the generation and analysis of a knockout mouse carrying a deletion of exon 3 in the parkin gene. F1 hybrid pa+/- mice were backcrossed to wild-type C57Bl/6 for three more generations to establish a pa-/-(F4) mouse line. The appearance of tyrosine hydroxylase-positive neurons was normal in young and aged pa-/- (F4) animals. Loss of parkin function in mice did not enhance vulnerability of dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. However, the pa-/- (F4) mice displayed impaired exploration and habituation to a new environment and exhibited thigmotaxis behaviour in the open field and Morris water maze. Abnormal anxiety-related behaviour of pa-/- (F4) mice was also observed in the light/dark exploration test paradigm. Dopamine metabolism was enhanced in the striatum of pa-/- (F4) mice, as revealed by increased homovanillic acid (HVA) content and a reduced ratio of dihydroxyphenylacetic acid (DOPAC)/HVA. The alterations found in the dopaminergic system could be responsible for the behavioural impairments of pa-/- (F4) mice. Consistent with a recent observation of cognitive dysfunction in parkin-linked patients with PD, our findings provide evidence of a physiological role of parkin in non-motor behaviour, possibly representing a disease stage that precedes dopaminergic neuron loss.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
  • Age Factors
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology*
  • Body Weight / drug effects
  • Body Weight / genetics
  • Brain / cytology
  • Brain Chemistry / drug effects
  • Brain Chemistry / genetics
  • Dopamine / metabolism
  • Dopamine Agents / pharmacology
  • Mental Disorders / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Motor Skills / drug effects
  • Motor Skills / physiology
  • Neurons / drug effects
  • Neurons / metabolism
  • Time Factors
  • Tyrosine 3-Monooxygenase / metabolism
  • Ubiquitin-Protein Ligases / deficiency*

Substances

  • Dopamine Agents
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Tyrosine 3-Monooxygenase
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Dopamine