Session Time: 1:45pm-3:15pm
Location: Hall 3FG
Objective: To study changes in neuronal morphology and neurotransmitter metabolism in the striatum of a pharmacological DYT12 mouse model after induction of a dystonic phenotype by motor stress.
Background: Patients with Rapid-Onset Dystonia-Parkinsonism (DYT12) carry a mutation of the α3 isoform of the Na+/K+-ATPase, which can be pharmacologically simulated through perfusion of ouabain into the striatum and cerebellum of wt mice. As seen in DYT12 patients, the development of a dystonic phenotype in ouabain-treated mice was induced by physical stress.
Methods: Striatum and cerebellum of wt mice were perfused over 72 h with NaCl (control) or ouabain via osmotic pumps, at a 24 h interval one group of ouabain-treated mice were subjected to motor stress in form of a Rotarod performance test and Pole test. A Dystonia Rating Scale (DRS) assessed the frequency and distribution of dystonia-like movements from 0-4 points. Mice were scored in a tail suspension test (TST) from 0-8 points for dystonia-like movements in forelimbs, hind limbs and trunc. A Golgi-Cox staining visualized medium spiny neurons (MSN) in the striatum and was evaluated via Sholl-analysis. Monoamine activity in the striatum was analyzed via HPLC.
Results: The DRS score and TST score in stressed mice were significantly higher than in unstressed mice (DRS: 3.0 ± 0.20 vs 2.1 ± 0.19, p < 0.01; TST: 5.50 ± 0.32 vs 3.77 ± 0.53, p < 0.005). Golgi-Cox staining showed a reduction in spine density, number of spines and dendrite lengths of MSN in both ouabain-treated groups compared to NaCl-perfused control mice. Stress application did not lead to any additional structural alterations. HPLC analysis revealed that ouabain treatment only led to significant reduction in striatal dopamine (DA) levels in comparison to the control group (relative level: 0.55 ± 0.09 vs 1.0 ± 0.034, p < 0.05), however motor stress in ouabain mice restored DA activity almost to control levels (0.90 ± 0.08). A significant increase in striatal DOPAC and HVA levels as well as DA turnover ratios in both ouabain-treated groups was recorded compared to NaCl-perfused mice.
Conclusions: A dystonic phenotype was successfully induced by application of motor stress in this DYT12 mouse model. Alterations in the major striatal output neurons are hinting at significant functional abnormalities. Furthermore, DA dysregulation may play a central role in DYT12 disease development.
To cite this abstract in AMA style:L. Rauschenberger, Y. Al-Zuraiqi, J. Volkmann, C.W. Ip. Striatum of the ouabain-induced pharmacological DYT12 mouse model is affected by structural and metabolic abnormalities [abstract]. Mov Disord. 2018; 33 (suppl 2). https://www.mdsabstracts.org/abstract/striatum-of-the-ouabain-induced-pharmacological-dyt12-mouse-model-is-affected-by-structural-and-metabolic-abnormalities/. Accessed December 9, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/striatum-of-the-ouabain-induced-pharmacological-dyt12-mouse-model-is-affected-by-structural-and-metabolic-abnormalities/