Objective: To induce a dystonic phenotype in DYT1 (hΔGAG3) mice through peripheral trauma in order to analyze metabolic and structural alterations in the striatum.

Background: DYT1 is the most common form of hereditary dystonia caused by mutations in the Tor1a gene with a penetrance of only 30%. hΔGAG3 mice express the human torsinA mutation and do not show a dystonic phenotype in their naïve state. We aimed to examine whether environmental factors have a lasting effect on the development of dystonic symptoms supporting a two hit hypothesis. Therefore, we induced a peripheral nerve trauma in genetically predisposed hΔGAG3 mice.

Methods: We analyzed wildtype (wt) and hΔGAG3 mice (tg) subdivided into naïve, sham and groups with nerve trauma. Dystonia-like movements were defined as clenching and retraction of hindlimbs. Before and after unilateral sciatic nerve crush injury dystonia-like movements were scored during tail suspension test (TST) according to frequency and duration with a 0-5 points scoring system. Rotarod Performance Test (RPT) was applied before nerve injury and afterwards over 12 weeks. After brain dissection at the end of week 12 the striatum was analyzed via HPLC to determine the quantity of catecholamines.

Results: While both tg and wt mice developed dystonia-like movements 2 weeks after nerve injury during TST, tg mice displayed a significantly higher dystonia score starting at week 3 compared to wt mice (week 12: 2,2±0,6 vs 0,4±0,2 points, P<0,05). Dystonic movements in wt mice declined after week 11 almost to control levels. RPT showed no significant differences in the latency to fall in tg and wt mice after nerve trauma. Dopamine (DA) level of the contralateral striatum showed a 23.3% reduction in sham-operated tg mice compared to wt mice. Crush injury led to a non-significant increase of DA levels by 42.4% in tg mice and mild decrease in wt mice.

Conclusions: Our study indicates that peripheral nerve trauma is able to trigger dystonic movements in genetically predisposed, asymptomatic hΔGAG3 mice. Preliminarily, monoamine analysis hints at a possible striatal dopamine dysregulation in hΔGAG3 mice. In summary, this study supports a potential two hit hypothesis in DYT1 dystonia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/peripheral-trauma-elicits-a-dystonic-phenotype-in-a-dyt1-transgenic-mouse-model/