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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- "Most of the existing rodent models of dystonia, where the cerebellum is suggested to contribute to the motor symptoms, exhibit generalized twisting and abnormal movements (Wilson and Hess, 2013). In genetically dystonic rats, which exhibit generalized dystonic movements, cerebellectomy improves the motor phenotype and allows the rats to survive to adulthood (LeDoux et al., 1995). In tottering mice, which exhibit episodic generalized dystonic movements caused by a mutation in a voltage-gated calcium channel gene (Doyle et al., 1997; Campbell and Hess, 1999), during dystonic episodes, electromyographic activity becomes significantly coherent with activity in the cerebellar cortex (Chen et al., 2009). "
ABSTRACT: Recent evidence suggests that dystonia, a movement disorder characterized by sustained involuntary muscle contractions, can be associated with cerebellar abnormalities. The basis for how functional changes in the cerebellum can cause dystonia is poorly understood. Here we identify alterations in physiology in Atcay(ji-hes) mice which in addition to ataxia, have an abnormal gait with hind limb extension and toe walking, reminiscent of human dystonic gait. No morphological abnormalities in the brain accompany the dystonia, but partial cerebellectomy causes resolution of the stiff-legged gait, suggesting that cerebellar dysfunction contributes to the dystonic gait of Atcay(ji-hes) mice. Recordings from Purkinje and deep cerebellar nuclear (DCN) neurons in acute brain slices were used to determine the physiological correlates of dystonia in the Atcay(ji-hes) mice. Approximately 50% of cerebellar Purkinje neurons fail to display the normal repetitive firing characteristic of these cells. In addition, DCN neurons exhibit increased intrinsic firing frequencies with a subset of neurons displaying bursts of action potentials. This increased intrinsic excitability of DCN neurons is accompanied by a reduction in after-hyperpolarization currents mediated by small-conductance calcium-activated potassium (SK) channels. An activator of SK channels reduces DCN neuron firing frequency in acute cerebellar slices and improves the dystonic gait of Atcay(ji-hes) mice. These results suggest that a combination of reduced Purkinje neuron activity and increased DCN intrinsic excitability can result in a combination of ataxia and a dystonia-like gait in mice.Neurobiology of Disease 04/2014; 67. DOI:10.1016/j.nbd.2014.03.020 · 5.20 Impact Factor
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- "In a genetically dystonic rat that harbors a mutation in the gene caytaxin, cerebellectomy eliminates the motor symptoms and rescues the juvenile lethality , . Electronic lesions of dorsal portions of the lateral vestibular nuclei (dLV), which receive input from the Purkinje cells, are associated with the greatest improvement in this rat . The Purkinje cells send the major inhibitory signal from the cerebellum to the deep cerebellar nuclei, which is mediated by the neurotransmitter γ-aminobutyric acid (GABA). "
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 03/2011; 6(3):e18357. DOI:10.1371/journal.pone.0018357 · 3.23 Impact Factor
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- "Microscopic analysis of cresyl violet, hematoxylin and eosin, Luxol fast blue, periodic acid- Schiff and silver-stained central and peripheral nervous tissues from dt rats has shown no differences from normals (Lorden et al. 1984, LeDoux et al. 1995). Because they are a central component of the basal ganglia, the morphology of striatal neurons was examined with Golgi impregnation in both dt and normal rats; no abnormalities were detected in the mutants (McKeon et al. 1984). "
ABSTRACT: Dystonia is a motor sign characterized by involuntary muscle contractions which produce abnormal postures. Genetic factors contribute significantly to primary dystonia. In comparison, secondary dystonia can be caused by a wide variety of metabolic, structural, infectious, toxic and inflammatory insults to the nervous system. Although classically ascribed to dysfunction of the basal ganglia, studies of diverse animal models have pointed out that dystonia is a network disorder with important contributions from abnormal olivocerebellar signaling. In particular, work with the dystonic (dt) rat has engendered dramatic paradigm shifts in dystonia research. The dt rat manifests generalized dystonia caused by deficiency of the neuronally restricted protein caytaxin. Electrophysiological and biochemical studies have shown that defects at the climbing fiber-Purkinje cell synapse in the dt rat lead to abnormal bursting firing patterns in the cerebellar nuclei, which increases linearly with postnatal age. In a general sense, the dt rat has shown the scientific and clinical communities that dystonia can arise from dysfunctional cerebellar cortex. Furthermore, work with the dt rat has provided evidence that dystonia (1) is a neurodevelopmental network disorder and (2) can be driven by abnormal cerebellar output. In large part, work with other animal models has expanded upon studies in the dt rat and shown that primary dystonia is a multi-nodal network disorder associated with defective sensorimotor integration. In addition, experiments in genetically engineered models have been used to examine the underlying cellular pathologies that drive primary dystonia. This article is part of a Special Issue entitled "Advances in dystonia".Neurobiology of Disease 11/2010; 42(2):152-61. DOI:10.1016/j.nbd.2010.11.006 · 5.20 Impact Factor