Evidence for dysfunction of the nigrostriatal pathway in the R6/1 line of transgenic Huntington's disease mice.
The present multidisciplinary study examined nigrostriatal dopamine and striatal amino acid transmission in the R6/1 line of transgenic Huntington's disease (HD) mice expressing exon 1 of the HD gene with 115 CAG repeats. Although the number of tyrosine hydroxylase-positive neurons was not reduced and nigrostriatal connectivity remained intact in 16-week-old R6/1 mice, the size of tyrosine hydroxylase-positive neurons in the substantia nigra was reduced by 15%, and approximately 30% of these cells exhibited aggregated huntingtin. In addition, using in vivo microdialysis, we found that basal extracellular striatal dopamine levels were reduced by 70% in R6/1 mice compared to their wild-type littermates. Intrastriatal perfusion with malonate in R6/1 mice resulted in a short-lasting, attenuated increase in local dopamine release compared to wild-type mice. Furthermore, the size of the malonate-induced striatal lesion was 80% smaller in these animals. Taken together, these findings suggest that a functional deficit in nigrostriatal dopamine transmission may contribute to the behavioral phenotype and the resistance to malonate-induced neurotoxicity characteristic of R6/1 HD mice.
Petersén
A
A
Section for Neuronal Survival, Wallenberg Neuroscience Center, Lund University, Sweden.
Puschban
Z
Z
Lotharius
J
J
NicNiocaill
B
B
Wiekop
P
P
O'Connor
W T
WT
Brundin
P
P
D000818:Animals; D002452:Cell Count; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005456:Fluorescent Dyes; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology*; D008314:Malonates / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D017551:Microdialysis; D009434:Neural Pathways / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D013266:Stilbamidines; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D005456:Fluorescent Dyes; D008314:Malonates; D013266:Stilbamidines; C030290:malonic acid; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine