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• W2334259710 abstract "Review of Calderon DP, Fremont R, Kraenzlin F, Khodakhah K. The neural substrates of rapid-onset dystonia-Parkinsonism. Nat Neurosci. 2011;14(3):357-365. Rapid-onset dystonia-Parkinsonism (RDP) is a relatively rare type of hereditary dystonia involving a loss of function mutation in the sodium-potassium ATPase pump. Patients with this condition interestingly demonstrate episodic manifestations of both dystonia and Parkinsonism during periods of extreme stress. Genetic mouse models of this disorder have been created; however, the primary features of the disease are not exhibited. It is possible, however, to selectively block the sodium-potassium pump in a location-dependent fashion with infusion of an antagonist. In a unique study, Calderon et al have now blocked the α3 isoform of the mouse sodium-potassium ATPase pump using stereotactic infusions of ouabain. This enabled the authors to create a pharmacologic animal model of RDP, which demonstrates many of the same features of the disease found in humans. The authors performed bilateral stereotactic placement of perfusion catheters into the basal ganglia region of the mouse brain (likely affecting the caudate/putamen and globus pallidus). A single catheter was also placed in the midline region of the deep cerebellar nuclei. Perfusion of ouabain could then be performed in a controlled manner and differentially between the 2 structures. For example, sole perfusion of ouabain into the basal ganglia produced features of Parkinsonism including rigidity, tremor, postural instability, and reduced locomotion. However, this sole perfusion of the basal ganglia did not produce any involuntary dystonic movements or stress-induced dystonia. On the other hand, isolated perfusion of the cerebellum with ouabain did produce ataxia and dystonic postures in the mice, without the akinesia and rigidity seen in basal ganglia perfusion. Joint perfusion of both the basal ganglia and cerebellum with ouabain also produced gait difficulties and reduced movement overall. At low levels of joint perfusion (18 ng/hr), the mice exhibited stable levels of mild dyskinesia, but no dystonia. Similar to RDP symptoms in humans, stress (electric foot-shocks) subsequently produced persistent dystonic posturing, with EMG recordings verifying agonist/antagonist group co-contractions up to 3 days after the stress exposure. Additionally, with solitary cerebellar ouabain perfusion, the mice showed EEG changes specifically in cerebellum with only mild alterations in cortical EEG. The mice continue to exhibit dystonia even during tetrodotoxin blockade of the cortex, implying the causal relationship of abnormal cerebellar activity in this type of clinical dystonia. Interestingly in these animals, thermocoagulation lesioning of the centrolateral nucleus (effectively disconnecting the cerebellar-basal ganglia linkage) altered their motor symptoms exhibited with ouabain perfusion into the cerebellum. The lesioned animals demonstrated much reduced motor disturbances, and no signs of dystonia. Calderon et al have demonstrated the prominent role the cerebellum plays in the development of stress-induced dystonia in this animal model of RDP. Animal models of dystonia have proven difficult to develop, and this described selective and reversible blockade technique is a great step forward. The development of new and or novel neuromodulation therapies for the movement disorders will increasingly base new therapies on this type of systems-neuroscience investigation. W. S. AndersonFigure: A, RDP mouse model undergoing perfusion of the basal ganglia and cerebellum with ouabain at 24 hours of infusion. Stress induces dystonic posturing. B, effect of stress on locomotion in a variety of ouabain or vehicle perfusion conditions. Significant difference in locomotion for selective perfusion of ouabain into basal ganglia pre- and poststress. A similar plot is demonstrated for dystonia score, where a large significant pre- and poststress difference occurs in concurrent perfusion of the basal ganglia and cerebellum with ouabain." @default.
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• W2334259710 date "2011-08-01" @default.
• W2334259710 modified "2023-09-23" @default.
• W2334259710 title "A New Mouse Model of Dystonia" @default.
• W2334259710 doi "https://doi.org/10.1227/01.neu.0000400015.31648.e4" @default.
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