Objective: Establishment and characterization of a DYT1 rat model with dystonia-like movements after sciatic nerve crush injury.

Background: Penetrance of DYT1 dystonia is markedly reduced with 30-40%. To verify if environmental factors can trigger dystonia in genetically predisposed DYT1 gene carrier (second hit hypothesis), we aimed to induce dystonia in a transgenic DYT1 rat model (ΔETorA), that harbors the full human mutant Tor1A gene and is asymptomatic per se, by a peripheral nerve injury.

Methods: Dystonia-like movements of the hindlimbs during tail suspension were scored before and after unilateral sciatic nerve crush injury with a new scoring system at week 2, 5, 9 and 12. Nerve conduction velocity (NCV) and compound muscle action potentials (CMAP) of wildtype (wt) and ΔETorA rat sciatic nerves were evaluated by in vivo electroneurographic recordings (ENG) 12 weeks after nerve injury.

Results: Both wt and ΔETorA rats developed dystonia-like movements after nerve injury with a maximum score at week 2. In wt rats, the score then continuously decreased to a minimum at week 9 (0.4 ± 0.3) and stayed at this low level, that was comparable to naïve rats, until week 12 (0.6 ± 0.3). However, compared to this group a significantly higher dystonia-like movement score was observed in nerve injured ΔETorA rats at week 9 (1.9 ± 0.4) (p< 0.01) and at week 12 (1.9 ± 0.4) (p< 0.05). Moreover, after nerve injury a higher penetrance of dystonia-like movements was found in ΔETorA rats (70%) compared to wt rats (30%). Additionally, a spreading of dystonia-like movements to the contralateral hindlimb was seen in 35% of nerve injured ΔETorA rats but not in nerve injured wt rats.

ENG recordings didn`t show any significant differences in NCV or CMAP comparing wt rats with ΔETorA rats, 12 weeks after nerve injury, although both genotypes demonstrated slower NCV and reduced CMAP amplitudes after nerve crush compared to naïve controls of both genotypes.

Conclusions: Our data indicate that a peripheral nerve trauma can trigger dystonia-like movements in genetically predisposed ΔETorA rats, which supports the “second hit” hypothesis. Functional assessment by ENG excluded impaired nerve regeneration after injury as a reason for a higher dystonia-like movement score in ΔETorA rats.  

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dystonia-like-phenotype-in-a-dyt1-rat-model-after-peripheral-trauma/