Neuroanatomical substrates for paroxysmal dyskinesia in lethargic mice

Abstract

The paroxysmal dyskinesias are a group of neurological disorders described by intermittent attacks of involuntary abnormal movements superimposed on a relatively normal baseline. The neuroanatomical substrates for these attacks are not fully understood, though available evidence from studies of affected people and animal models points to dysfunction in the basal ganglia or cerebellum. In the current studies, the anatomical basis for paroxysmal dyskinesias in lethargic mice was determined via histochemical methods sensitive to changes in regional brain activity followed by surgical elimination of the suspected source. Cytochrome oxidase histochemistry revealed increased activity in the red nucleus. Surgical removal of the cerebellum worsened ataxia but eliminated paroxysmal dyskinesias. These studies support the hypothesis that abnormal cerebellar output contributes to paroxysmal dyskinesias.

Figure 1.

Abnormal movement scores before and after cerebellectomy in lethargic mice. Results show average (±SEM) abnormal movement scores before (upper panel) and after (lower panel) cerebellectomy in 4 lethargic mice treated with saline (black bars) or caffeine (gray bars). Results for each type of abnormal movement were analyzed separately by 2-way ANOVA with cerebellectomy and drug treatment as the main factors. Asterisks show significant differences between saline and drug-treated animals, while daggers show significant differences between unoperated and operated mice by post-hoc Tukey-tests (p<0.05).

Figure 2.

Abnormal movement scores before and after cerebellectomy in normal mice. Results show average (±SEM) abnormal movement scores before (upper panel) and after (lower panel) cerebellectomy in 6 normal mice treated with saline (black bars) or ±BayK 8644 (gray bars). Results for each type of abnormal movement were analyzed separately by 2-way ANOVA with cerebellectomy and drug treatment as the main factors. Asterisks show significant differences between saline and drug-treated animals, while daggers show significant differences between unoperated and operated mice by post-hoc Tukey-tests (p<0.05).

Figure 3.

Motor function tests. Results show average (±SEM) for the cling test (upper panel) and activity chambers (lower panel) for 6 normal (black bars) and 4 lethargic (open bars) mice. Results for each motor test were analyzed separately by 2-way ANOVA with genotype and cerebellectomy as the main factors. The asterisk shows a significant difference for one group compared with all other groups (p<0.05).

Figure 4.

Gross brain specimen after cerebellectomy. A normal mouse is shown in panels A (posterior) and B (lateral), while an operated mouse is shown in panels C (posterior) and D (lateral). The cerebellum has been completely removed, providing an unobstructed view of the tectum.