Objective: To study if a mild stressful trigger by motor activity leads to development of dystonia-like movements in a pharmacological mouse model for DYT12.

Background: DYT12 dystonia, linked to loss-of-function of the ATP1α3 gene, is characterized by generalized dystonic postures and parkinsonian symptoms that abruptly develop after a stressful event. Previous publications reported the development of a pharmacological DYT12 model by perfusion of ouabain, a selective ATP1α3-blocker, into basal ganglia and cerebellum of wt mice via osmotic pumps that lead to dystonia-like postures and parkinsonian symptoms if mice were subjected to severe stress by electric foot shocks.

Methods: Ouabain concentrations between 9 – 36 ng/h in cerebellum and basal ganglia were tested with a final concentration of 11.2 ng/h being used. As motor stressors, ouabain-perfused mice were repeatedly subjected to the Rotarod Performance test and Pole test. The exhibited phenotype was longitudinally assessed through Open Field analysis, video recordings of spontaneous movements and tail suspension test over 72 h. Motor symptoms were evaluated by an adapted Motor Behavioral Scale with 0-2 points per category to assess general activity, postural instability, hind limb dystonia and truncal dystonia. A new 8-point scoring system to assess dystonia-like movements was applied for the tail suspension test: crossing of hyperextended forelimbs as well as tonic flexion, scored from 0-4 points depending on severity and duration; hyperextension of hindlimbs and clasping behavior was scored from 0-3 points; 1 point was given for truncal distortion.

Results: Abnormal motor behavior observed in ouabain-perfused mice were hyperextensions of limbs, kyphosis, reduced locomotion and postural instability. The Motor Behavioral Scale in stressed mice was significantly higher than in unstressed mice (5.06 ± 0.22 vs 3.19 ± 0.36, respectively; P<0.0001). Open Field analysis showed reduced locomotion in stressed mice with 16.7 % less distance moved than unstressed animals. Scoring of the mice in tail suspension placed the stressed group at 5.50 ± 0.32 compared to 3.77 ± 0.53 in the unstressed group (P<0,005).

Conclusions: This modified pharmacologic mouse model for DYT12 with reduced ouabain-dosage exhibits dystonia-like movements and a parkinsonian phenotype with significant increase of symptoms when subjected to motor stress.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/motor-stress-elicits-dystonia-like-movements-in-a-pharmacological-mouse-model-for-rapid-onset-dystonia-parkinsonism-dyt12/