17550429

pubmed:Citation

3

Early onset torsion dystonia, the most common form of hereditary primary dystonia, is caused by a mutation in the TOR1A gene, which codes for the protein torsinA. This form of dystonia is referred to as DYT1. We have used a transgenic mouse model of DYT1 dystonia [human mutant-type (hMT)1 mice] to examine the effect of the mutant human torsinA protein on striatal dopaminergic function. Analysis of striatal tissue dopamine (DA) and metabolites using HPLC revealed no difference between hMT1 mice and their non-transgenic littermates. Pre-synaptic DA transporters were studied using in vitro autoradiography with [(3)H]mazindol, a ligand for the membrane DA transporter, and [(3)H]dihydrotetrabenazine, a ligand for the vesicular monoamine transporter. No difference in the density of striatal DA transporter or vesicular monoamine transporter binding sites was observed. Post-synaptic receptors were studied using [(3)H]SCH-23390, a ligand for D(1) class receptors, [(3)H]YM-09151-2 and a ligand for D(2) class receptors. There were again no differences in the density of striatal binding sites for these ligands. Using in vivo microdialysis in awake animals, we studied basal as well as amphetamine-stimulated striatal extracellular DA levels. Basal extracellular DA levels were similar, but the response to amphetamine was markedly attenuated in the hMT1 mice compared with their non-transgenic littermates (253 +/- 71% vs. 561 +/- 132%, p < 0.05, two-way anova). These observations suggest that the mutation in the torsinA protein responsible for DYT1 dystonia may interfere with transport or release of DA, but does not alter pre-synaptic transporters or post-synaptic DA receptors. The defect in DA release as observed may contribute to the abnormalities in motor learning as previously documented in this transgenic mouse model, and may contribute to the clinical symptoms of the human disorder.

eng

IM

MEDLINE

0022-3042

Print

NLM

783-8

pubmed-meshheading:17550429-Animals, pubmed-meshheading:17550429-Binding, Competitive, pubmed-meshheading:17550429-Corpus Striatum, pubmed-meshheading:17550429-Disease Models, Animal, pubmed-meshheading:17550429-Dopamine, pubmed-meshheading:17550429-Dopamine Plasma Membrane Transport Proteins, pubmed-meshheading:17550429-Dystonia Musculorum Deformans, pubmed-meshheading:17550429-Genetic Predisposition to Disease, pubmed-meshheading:17550429-Humans, pubmed-meshheading:17550429-Ligands, pubmed-meshheading:17550429-Mice, pubmed-meshheading:17550429-Mice, Transgenic, pubmed-meshheading:17550429-Molecular Chaperones, pubmed-meshheading:17550429-Mutation, pubmed-meshheading:17550429-Presynaptic Terminals, pubmed-meshheading:17550429-Radioligand Assay, pubmed-meshheading:17550429-Receptors, Dopamine, pubmed-meshheading:17550429-Synaptic Transmission, pubmed-meshheading:17550429-Transgenes

Dopamine release is impaired in a mouse model of DYT1 dystonia.

Journal Article, Research Support, N.I.H., Extramural