Motor tics evoked by striatal disinhibition in the rat

Abstract

Motor tics are sudden, brief, repetitive movements that constitute the main symptom of Tourette syndrome (TS). Multiple lines of evidence suggest the involvement of the cortico-basal ganglia system, and in particular the basal ganglia input structure-the striatum in tic formation. The striatum receives somatotopically organized cortical projections and contains an internal GABAergic network of interneurons and projection neurons' collaterals. Disruption of local striatal GABAergic connectivity has been associated with TS and was found to induce abnormal movements in model animals. We have previously described the behavioral and neurophysiological characteristics of motor tics induced in monkeys by local striatal microinjections of the GABAA antagonist bicuculline. In the current study we explored the abnormal movements induced by a similar manipulation in freely moving rats. We targeted microinjections to different parts of the dorsal striatum, and examined the effects of this manipulation on the induced tic properties, such as latency, duration, and somatic localization. Tics induced by striatal disinhibition in monkeys and rats shared multiple properties: tics began within several minutes after microinjection, were expressed solely in the contralateral side, and waxed and waned around a mean inter-tic interval of 1-4 s. A clear somatotopic organization was observed only in rats, where injections to the anterior or posterior striatum led to tics in the forelimb or hindlimb areas, respectively. These results suggest that striatal disinhibition in the rat may be used to model motor tics such as observed in TS. Establishing this reliable and accessible animal model could facilitate the study of the neural mechanisms underlying motor tics, and the testing of potential therapies for tic disorders.

Keywords: GABA; Tourette syndrome; basal ganglia; bicuculline; striatum.

Figure 1

Histology. Nissl staining of coronal sections of the right hemisphere from an injected rat. A cannula lesion can be seen in the (A) anterior and (B) posterior striatum, black arrows point to the corresponding injection sites.

Figure 2

Bicuculline-induced motor tics period. (A) Latency to tic onset (time difference between microinjection onset and the appearance of the first motor tic). (B) Duration of tic expression (time difference between the first and last observed tics). In both graphs, results are shown separately for sessions in which the microinjection was targeted to the anterior (blue marker) or posterior (red marker) striatum. Horizontal lines indicate the group mean. ^*p < 0.01.

Figure 3

Temporal properties of motor tics. (A) An example of tic rate of an entire session (injection to the anterior striatum which induced forelimb tics). Horizontal red line indicates the injection time. Red arrow indicates time of first tic. (B) Histogram of the inter-tic intervals (ITIs) taken from the session presented in (A). (C,D) A comparison of the (C) mean and (D) coefficient of variation (CV) of the ITIs observed in monkeys and rats throughout all the sessions. Horizontal lines indicate the group mean.

Figure 4

Tic somatic localization. Behavioral effects of bicuculline microinjections into the anterior (left) or posterior (right) striatum, classified according to the extent of localization of motor tics.

Figure 5

Somatotopic organization of tics. Percentages of bicuculline microinjections into the anterior (blue) or posterior (red) striatum inducing tics in different body parts. (A) Body part in which the first tics following microinjection were observed. (B) All body parts in which tics were observed at any stage during the session.