Paroxysmal dyskinesias in mice

Abstract

Animal models of human disease are important tools for revealing the underlying mechanisms of pathophysiology and developing therapeutic strategies. Several unique mouse calcium channel mutants have been identified with nonepileptic, episodic dyskinetic movements that are phenotypically similar to human paroxysmal dyskinesias. In this report, video demonstrations of these motor attacks are provided for two previously described mouse mutants, tottering and lethargic, as well as a new one, rocker. Semiquantitative comparisons using two different rating scales reveal differences in attack morphology, severity, and duration among the strains. These mice provide three independent models of paroxysmal dyskinesia and support for prior proposals that channelopathies may underlie the human disorders. Keywordstottering; lethargic; rocker; paroxysmal dyskinesia; dystonia; channelopathyThe paroxysmal dyskinesias are a group of rare disorders characterized by intermittent attacks of involuntary abnormal movements.1 -3 These movements are often dystonic or choreiform, but may include a variety of other abnormalities. Unlike epilepsy, they are not associated with abnormal activity on electroencephalograms (EEGs).The paroxysmal dyskinesias are divided currently into three groups, which are based on the triggers of attacks, average attack duration, predominant morphology, and other features. [1][2][3] Paroxysmal nonkinesigenic dyskinesia is precipitated by stress, caffeine, or alcohol. The frequency of attacks ranges from a few per day to a few per year, with a duration of a few hours to several days. In contrast, attacks of paroxysmal kinesigenic dyskinesia are brought on by sudden movement, startle, and even passive manipulation of muscles. They are more frequent but shorter, occur many times per day, and last less than a few minutes each. In paroxysmal exertional dyskinesia, attacks are caused by prolonged exercise. Attacks are of intermediate duration with a frequency tied to the level of physical exertion.Recent studies also have revealed paroxysmal dyskinesias in certain strains of mice. The tottering mouse carries a mutation in the Cacna1a gene, which encodes a calcium channel subunit. 4,5 These mutants exhibit mild ataxia at baseline with intermittent attacks of severely disabling dyskinetic movements. 6,7 The lethargic mouse carries a mutation in the Cacnb4 gene, which encodes a different calcium channel subunit. 8 These mutants exhibit mild ataxia and a hypokinetic syndrome at baseline with intermittent attacks of dyskinetic movements. 9 The purpose of this report is to provide a video demonstration of the motor phenotypes of tottering and lethargic mice. In addition, we describe paroxysmal dyskinesia in a third mutant mouse, rocker, which also carries a mutation in the Cacna1a gene, but different from that in tottering

Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis

“…We speculate that in mut-Tg mice, neurons are more vulnerable to elevated calcium levels and thus develop hyperexcitability when challenged with coffee, alcohol, or stress. In our mutant PNKD mouse model and other generalized dystonia mouse models, dysregulated dopamine signaling has been demonstrated in the striatum (10,(33)(34)(35)(36)(37).…”

Purkinje Cell Input to Cerebellar Nuclei in Tottering: Ultrastructure and Physiology

“…The episodes of paroxysmal dyskinesia can be reliably triggered by environmental challenges [4][5][6] and are distinguished from the permanent ataxia by the sequence of three stages of behavioral abnormalities, which start at the hind limbs, then gradually spread to the front limbs, and eventually also reach the head and neck. These motor attacks, which typically occur approximately one to two times per day and can last up to 40 min, include irregular jerky movements, slow writhing motions, and involuntary stretching of the muscles [1,3,7]. In between these episodes, tg mice are mildly ataxic in that they show an abnormal gait and decreased motor performance and learning [8][9][10].…”

The first knockin mouse model of episodic ataxia type 2

“…Tottering , rocker , and rolling Nagoya mice all carry spontaneous missense mutations in Cacna1a and homozygotes of these strains all exhibit a clear neurobehavioral phenotype that includes cerebellar ataxia and paroxysmal dystonia (Oda, 1973, Shirley et al, 2008). Leaner mice that carry a Cacna1a nonsense truncation mutation (Meier and MacPike, 1971, Fletcher et al, 1996) which results in a 40–60% reduction in the PC Ca V 2.1 Ca 2+ current similar to the reduction in current measured in EA2/EA2 mouse PCs (Dove et al, 1998, Wakamori et al, 1998), suffer from a severe phenotype with chronic dystonia similar to the severe phenotype observed in Cacna1a knockout mice.…”

“…Indeed, selective elimination of Ca V 2.1 channels from PCs causes a severe and chronic motor syndrome in mice that includes ataxia (Mark et al, 2011, Todorov et al, 2012). In other spontaneous mouse mutants with point mutations within Cacna1a that lead to moderately hypoconductive Ca V 2.1 channels, the motor dysfunction is somewhat less severe with both chronic and episodic components (Wakamori et al, 1998, Kodama et al, 2006, Shirley et al, 2008). However, in the heterozygous state, where one wild-type Cacna1a allele remains, mutant mice have normal motor function.…”