Electromyographic evidence in support of a knock-in mouse model of DYT1 Dystonia

Abstract

Introduction: DYT1 dystonia is an autosomal-dominant movement disorder characterized by abnormal, often repetitive, movements and postures. Its hallmark feature is sustained or intermittent contractions of muscles involving co-contractions of antagonist muscle pairs. The symptoms are relieved with the anticholinergic drug trihexyphenidyl. The primary mutation is a trinucleotide deletion (ΔGAG) in DYT1/TOR1A, which codes for torsinA. Previous studies showed that (1) heterozygous Dyt1 ΔGAG knock-in mice, which have an analogous mutation in the endogenous gene, exhibit motor deficits and altered corticostriatal synaptic plasticity in the brain and (2) these deficits can be rescued by trihexyphenidyl. However, brain imaging studies suggest that the Dyt1 knock-in mouse models nonmanifesting mutation carriers of DYT1 dystonia. The aim of this work was to examine the hallmark features of DYT1 dystonia in the Dyt1 knock-in mice by analyzing muscular activities.

Methods: Wireless telemetry devices with biopotential channels were implanted to the bicep and the rectus femori muscles in Dyt1 knock-in mice, and muscular activities were recorded before and after trihexyphenidyl administration.

Results: (1) Consistent with DYT1 dystonia patients, Dyt1 knock-in mice showed sustained contractions and co-contractions of the antagonistic bicep femoris and rectus femoris. (2) The abnormal muscle contractions were normalized by trihexyphenidyl.

Conclusion: The results suggest that the motor deficits in Dyt1 knock-in mice are likely produced by abnormal muscle contractions, and Dyt1 knock-in mice can potentially be used as a manifesting disease model to study pathophysiology and develop novel therapeutics. © 2016 International Parkinson and Movement Disorder Society.

Keywords: DYT1; anticholinergic; dystonia; electromyography; muscle contraction.

Fig 1

Representative EMG traces of dystonic muscle phenotypes examined. A. Schematic representation of the experimental design. B. An EMG trace of a normal muscle contraction from a WT mouse (rectus femoris). C. An EMG trace of a sustained muscle contraction from a Dyt1 KI mouse (rectus femoris). D. An EMG trace of a co-contraction of the agonistic muscle pair from a Dyt1 KI mouse. The left traces were obtained from the rectus femoris and the biceps femoris in the same scale as B and C. The yellow-shaded traces on the right were enlarged to show co-contractions at the faster time scale on the right. The arrows show the agonist and antagonist muscle activities coincide. Averaged power spectra before (E) and after THP treatment (H) for WT and KI mice ±1 STD (shaded regions) from both agonist and antagonist muscles. Mean power frequency for KI and WT mice before (F) and after THP treatment (I) shows no significant difference between KI and WT mice. Median power frequency for KI and WT mice before (G) and after THP treatment (J) shows no significant difference between KI and WT mice.

Fig 2

Sustained contractions in Dyt1 KI and WT mice and the effect of THP treatment. Examination of sustained contractions revealed a significantly increased number in Dyt1 KI mice compared to WT mice (A). After treatment of Dyt1 KI and WT mice with THP, there was no statistical difference between groups on the first or second day of treatment (B). Data is presented using a box and whisker plot, where the box represents the 25^th to 75^th percentile, the horizontal line within the box represents the medium, and the whiskers extend to include the minimum and maximum value. *: p < 0.05.

Fig. 3

Co-contractions in Dyt1 KI and WT mice and the effect of THP treatment. A. Averaged EMG normalized cross-correlation before THP treatment revealed a significant difference at lag τ = 0 between WT and KI mice, which was indicative of co-contractions in KI mice. B. Individual Fisher transformed histograms of cross-correlation coefficients at τ = 0 for KI mice (n = 7) and WT mice (n = 4). C, D. After THP treatment there was a general normalization of lag at τ = 0 between WT and KI mice. E. Comparison of the absolute values of the median (peak) correlation coefficients at τ = 0 from panels (B) and (D). Circle markers represent individual peak values, black dashes show the means of the values plotted. Gray lines pair each mouse before and after treatment. The KI mice before THP treatment showed significantly high absolute value of the median correlation coefficient in comparison to other three groups (p < 0.05). On the other hand, WT mice showed no significant alteration before and after THP treatment (p = 0.41). *: p < 0.05.