Objective: The aim of present study was to (1) generate more powerful tests to detect robust behavioral alterations in the DYT1 knock-in mouse model of dystonia and to (2) examine the effects of the D2 receptor agonist quinpirole and of pharmacological inhibition of specific striatal interneurons.

Background: The pathophysiology of dystonia, characterized by sustained or intermittent muscle contractions causing twisting movements/postures, is poorly understood. Ex vivo studies in mouse models of DYT1 dystonia have shown an abnormal D2 receptor mediated release of acetylcholine from striatal interneurons. However, these mice were reported to not exhibit a dystonic phenotype in standard behavioral tests which limits their use for preclinical drug testing.

Methods: The DYT1 knock-in mouse model and corresponding wildtypes were tested on a sequence of challenging cognitive, motor and sensorimotor tests. Subsequently the acute effects of quinpirole (0.25 -1 mg/kg i.p.) and of pharmacological inhibition of specific striatal interneurons on motor behavior were determined.

Results: The adhesive removal test that explores sensorimotor connectivity revealed significant impairments in the DYT1 knock-in mice compared to controls. In order to further test sensorimotor function we developed the “adaptive rotating beam test (ARB)” which includes changing sensory input. DYT1 knock-in mice showed robust deficits in this test. The higher sensitivity of the ARB test was further validated in another model of movement disorders which has previously not shown a behavioral phenotype. DYT1 knock-in and wildtype mice showed a dose-dependently reduced performance on the ARB test after quinpirole injection. In the adhesive removal test, quinpirole improved the reaction time in DYT1 mice independently of dosage, while no effects were observed in the wildtype littermates. However, vehicle follow-up (post-drug control) trials suggested a habituation effect. Studies on pharmacological inhibition of specific striatal interneurons are ongoing.

Conclusions: The novel adaptive rotating beam test for the first time detected a robust phenotype in the DYT1 knock-in mice. Sensorimotor impairments in this model were further supported by deficits in the adhesive removal test. Acute systemic injections of quinpirole did not modulate this phenotype. Future studies will examine the pathophysiological substrate of sensorimotor deficits in dystonia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/robust-sensorimotor-deficits-in-a-knock-in-mouse-model-of-primary-torsion-dystonia/