Biochemical and autoradiographic studies of the central noradrenergic system in dystonia musculorum mutant mice.
The autosomal recessive mutation dystonia musculorum (dt(J)/dt(J)) causes degenerative alterations of peripheral and central sensory pathways leading to ataxia. To determine the consequences of this pathology on the central noradrenergic (NA) system, NA contents were measured by high-performance liquid chromatography (HPLC) in 22 brain regions and spinal cord, while NA transporters, or uptake sites, were evaluated by quantitative ligand binding autoradiography, using [3H]nisoxetine, in wild-type and dt(J)/dt(J) mutant mice. The only significant differences in NA contents between the two genotypes were increased levels in hypothalamus and mesencephalic dopaminergic regions A9/A10 of dt(J)/dt(J) mutants. The dt(J)/dt(J) spinal cord showed a similar result, but its NA content remained unchanged when taking into account its reduced volume. Binding to NA transporters revealed increased densities in sensory nuclei of cranial nerves, granular layer of the cerebellar cortex, as well as in cerebellar-related and basal ganglia structures, such as the lateral cuneate nucleus, pontine nuclei, substantia nigra, pontine reticular formation, median raphe nucleus and superior colliculus. Forebrain regions were relatively unaffected in the dt(J)/dt(J) mutants, although NA transporter densities were higher in piriform cortex, hippocampal subdivisions and ventro-anterior thalamic nucleus. In contrast, densities of NA transporters were decreased in hypothalamic subregions and in two ventrobasal thalamic nuclei. The results are discussed in relation to expression of the dystonin gene in normal brain, cellular defects resulting from the loss of gene transcription in the dt(J)/dt(J) mutation, functional circuits of the central nervous system and some of the phenotypical characteristics of dystonia musculorum mutants.
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Département de Physiologie, Centre de Recherche en Sciences Neurologiques, Faculté de Médecine, Université de Montréal, Quebec, H3C 3J7, Montréal, Canada.
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D000818:Animals; D001345:Autoradiography; D001923:Brain Chemistry; D002531:Cerebellum / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D004422:Dystonia Musculorum Deformans / Q000235:genetics / Q000378:metabolism*; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D009638:Norepinephrine / Q000032:analysis* / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D013116:Spinal Cord / Q000737:chemistry; D027981:Symporters / Q000032:analysis* / Q000378:metabolism; D014316:Tritium
D050484:Norepinephrine Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; D027981:Symporters; D005473:Fluoxetine; D014316:Tritium; C011386:nisoxetine; D009638:Norepinephrine