Selective elimination of cerebellar output in the genetically dystonic rat.
ABSTRACT The genetically dystonic (dt) rat, an autosomal recessive mutant, exhibits a progressive motor syndrome that resembles the generalized idiopathic dystonia seen in humans. Even with supportive measures, dt rats die before reaching maturity. A total cerebellectomy that includes the dorsal portions of the lateral vestibular nuclei (dLV) eliminates the dystonic motor syndrome of the dt rats, greatly improves motor function, and prevents early death. The selective elimination of cerebellar nuclei was used to determine the cerebellar components critical to the mutant's motor syndrome. Bilateral electrolytic and/or excitatory amino acid lesions of the medial cerebellar nucleus, nucleus interpositus, lateral cerebellar nucleus and dLV were created in separate groups of 15-day-old dt rats. Rats were observed for the presence of abnormal motor signs (falls, twists, clasps, pivots) and tested on several measures of motor performance (activity, climbing, righting, homing, hanging) before surgery and again on Postnatal Day 20. All nuclear lesions produced significant improvements in motor function and decreases in the frequency of abnormal motor signs. Electrolytic lesions of the dLV were associated with the greatest improvements.
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ABSTRACT: Dystonia is a prevalent neurological disorder characterized by abnormal co-contractions of antagonistic muscle groups that produce twisting movements and abnormal postures. The disorder may be inherited, arise sporadically, or result from brain insult. Dystonia is a heterogeneous disorder because patients may exhibit focal or generalized symptoms associated with abnormalities in many brain regions including basal ganglia and cerebellum. Elucidating the pathogenic mechanisms underlying dystonia has therefore been challenging. Animal models of dystonia exhibit similar heterogeneity and are useful for understanding pathogenesis. The neurochemical and neurophysiological abnormalities in rodents with idiopathic generalized dystonia suggest that dysfunctional output from basal ganglia, cerebellum, or from multiple systems is the cause of motor dysfunction. Findings from drug- or toxin-induced dystonia in rodents and nonhuman primates mirror the genetic models. The parallels between dystonia in humans and animals suggest that the models will continue to prove useful in determining pathogenesis. Furthermore, detailed characterization of the existing models of dystonia and the development of new models hold promise for the identification of novel therapeutics.NeuroRx 08/2005; 2(3):504-12.
Article: Altered dendritic morphology of Purkinje cells in Dyt1 ΔGAG knock-in and purkinje cell-specific Dyt1 conditional knockout mice.[show abstract] [hide abstract]
ABSTRACT: DYT1 early-onset generalized dystonia is a neurological movement disorder characterized by involuntary muscle contractions. It is caused by a trinucleotide deletion of a GAG (ΔGAG) in the DYT1 (TOR1A) gene encoding torsinA; the mouse homolog of this gene is Dyt1 (Tor1a). Although structural and functional alterations in the cerebellum have been reported in DYT1 dystonia, neuronal morphology has not been examined in vivo. In this study, we examined the morphology of the cerebellum in Dyt1 ΔGAG knock-in (KI) mice. Golgi staining of the cerebellum revealed a reduction in the length of primary dendrites and a decrease in the number of spines on the distal dendrites of Purkinje cells. To determine if this phenomenon was cell autonomous and mediated by a loss of torsinA function in Purkinje cells, we created a knockout of the Dyt1 gene only in Purkinje cells of mice. We found the Purkinje-cell specific Dyt1 conditional knockout (Dyt1 pKO) mice have similar alterations in Purkinje cell morphology, with shortened primary dendrites and decreased spines on the distal dendrites. These results suggest that the torsinA is important for the proper development of the cerebellum and a loss of this function in the Purkinje cells results in an alteration in dendritic structure.PLoS ONE 01/2011; 6(3):e18357. · 4.09 Impact Factor