Impaired Nigrostriatal Dopaminergic Neurotransmission in Huntington’s Disease: Insights from the R6/1 Transgenic Mouse Model
Gil-Mohapel J, Brocardo PS, Smith R, Lagerkvist S, Li JY and Petersén Å.
In H.T. Maldonado and I.M. Ortega (Eds.) Striatum: Anatomy, Functions and Role in Disease. New York, USA: Nova Publishers.
Background: Huntington’s disease (HD) is the most common polyglutamine neurodegenerative disorder. The mutation consists of an unstable expansion of CAG repeats within the coding region of the HD gene, which expresses the protein huntingtin. Although the abnormal protein is ubiquitously expressed throughout the organism, cell degeneration occurs mainly in the brain, particularly in the striatum. Motor disturbances, associated with the loss of voluntary movement coordination, are the classical symptoms of HD. Previous studies have shown that the nigrostriatal dopaminergic system is impaired in transgenic mouse models of HD. In this study, we have further characterized deficits in the regulation of the nigrostriatal dopaminergic pathway in R6/1 transgenic HD mice.
Results: We examined R6/1 mice at 18-19 weeks of age using in vivo microdialysis. Specifically, we analyzed the maximum capacity of the nigrostriatal neurons to release dopamine (DA) in the striatum following KCl-induced depolarization of the plasma membrane and after administration of amphetamine. We used high-performance liquid chromatography (HPLC) to measure the levels of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dialysis perfusates. Intrastriatal infusion of both KCl and amphetamine rapidly increased the extracellular levels of DA in the dialysates in both R6/1 and wild-type mice, but the increase was significantly greater in the wild-type animals. In addition, we assessed the total DA tissue levels in the striatum contralateral to the side where we had performed intracerebral dialysis. The striatal tissue levels of DA were significantly decreased in R6/1 mice as compared with their wild-type littermate controls. We also observed a significant and progressive reduction in the mRNA and protein levels of tyrosine hydroxylase (TH) in R6/1 mice compared to their wild-type littermates. This may be the underlying cause for the reduced levels of DA release and tissue content.
Conclusions: Our results support earlier observations indicating that the dopaminergic nigrostriatal pathway is severely affected in R6/1 transgenic HD mice. Based on the present study and previous literature that we review here, we suggest that a dysfunctional nigrostriatal dopaminergic pathway is likely to contribute to some of the symptoms associated with HD.