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

Abstract

Background 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 non-manifesting mutation carriers of DYT1 dystonia. Objectives 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 the Dyt1 knock-in mice, and the muscular activities were recorded before and after trihexyphenidyl administration. Results (1) Consistent with DYT1 dystonia patients, the 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. Conclusions The results suggest that the motor deficits in the Dyt1 knock-in mice are likely produced by the abnormal muscle contractions and the Dyt1 knock-in mice can potentially be used as a manifesting disease model to study the pathophysiology and to develop novel therapeutics.

In vivo imaging reveals impaired connectivity across cortical and subcortical networks in a mouse model of DYT1 dystonia

“…An alternative viewpoint is that the observations could be compensatory for the underlying pathophysiology. A number of studies have shown that cortico-striatal synaptic efficacy (i.e., LTD) and impaired motor function are restored in Dyt1 KI (Dang et al, 2012; DeAndrade et al, 2016; Maltese et al, 2014) and KO (Liang et al, 2014; Pappas et al, 2015) mice following the administration of anticholinergic therapeutics. As such, future studies focused on elucidating restorative effects of anticholinergic medications on functional connectivity abnormalities will prove to be important in supporting the position that impaired basal ganglia connectivity manifests as a function of disease-specific pathogenesis.…”

“…As described above, previous work has reported that Dyt1 KI mice elicit impaired inhibitory modulation of cortical evoked potentials via striatal HFS in vitro (Dang et al, 2012). Moreover, abnormal sensorimotor evoked functional connectivity may account for recent evidence that the Dyt1 KI mouse model elicits sustained EMG activity and intermittent co-contractions of the biceps and rectus femori muscles (DeAndrade et al, 2016). These findings are in line with previous human studies that have reported increased volumetric grey-matter changes and amplified somatosensory activation in accounting for the overflow of conflicting cortical motor commands (i.e., SI) in patients with writer’s cramp, orofacial dystonia, and focal hand dystonia (Dresel et al, 2006; Garraux et al, 2004; Lerner et al, 2004).…”

“…Although Dyt1 KI mice demonstrate hyperactive behavior and subtle motor impairments, they remain resistant to the expression of an overt contracture-like dystonic phenotype observed in other Tor1a KO mouse models (Liang et al, 2014; Pappas et al, 2015). Notably, however, recent intramuscular EMG evidence has shown that compared to WT mice, Dyt1 KI mice are characterized by an increase in sustained contractions and intermittent co-contractile properties of the bicep and rectus femori muscles (DeAndrade et al, 2016). Furthermore, such antagonistic electrical potential of opposing muscle groups is alleviated via the administration of anti-cholinergic therapeutics (DeAndrade et al, 2016).…”

“…Notably, however, recent intramuscular EMG evidence has shown that compared to WT mice, Dyt1 KI mice are characterized by an increase in sustained contractions and intermittent co-contractile properties of the bicep and rectus femori muscles (DeAndrade et al, 2016). Furthermore, such antagonistic electrical potential of opposing muscle groups is alleviated via the administration of anti-cholinergic therapeutics (DeAndrade et al, 2016). Second, in the current study mice were induced to resting-state using isoflurane anesthesia at 2% concentration and maintained in an unconscious state for the duration of the imaging protocol at concentrations between 1–1.5%.…”

“…In particular, the Dyt1 KI mouse model represents a genetically derived experimental corollary akin to most human DYT1 dystonia patients (Ozelius et al, 1997). As well, although not possessive of an unconcealed spasmodic or contracture-like behavioral phenotype (Breakefield et al, 2008), Dyt1 KI mice exhibit sustained electromyographic (EMG) potential and intermittent co-contractions of opposing muscle groups (DeAndrade et al, 2016), which is a core feature of human patients with dystonia (Berardelli et al, 1998; van der Kamp et al, 1989). Previous work using 18 fludeoxyglucose positron emission tomography (PET) in vivo has demonstrated increased regional metabolic activity in the cerebellar vermis of Dyt1 KI mice (Uluğ et al, 2011) and Tor1a heterozygous knock-out (Dyt1 KO) mice (Vo et al, 2015a).…”