The neurobiological basis for novel experimental therapeutics in dystonia

Abstract

Dystonia is a movement disorder characterized by involuntary muscle contractions, twisting movements, and abnormal postures that may affect one or multiple body regions. Dystonia is the third most common movement disorder after Parkinson's disease and essential tremor. Despite its relative frequency, small molecule therapeutics for dystonia are limited. Development of new therapeutics is further hampered by the heterogeneity of both clinical symptoms and etiologies in dystonia. Recent advances in both animal and cell-based models have helped clarify divergent etiologies in dystonia and have facilitated the identification of new therapeutic targets. Advances in medicinal chemistry have also made available novel compounds for testing in biochemical, physiological, and behavioral models of dystonia. Here, we briefly review motor circuit anatomy and the anatomical and functional abnormalities in dystonia. We then discuss recently identified therapeutic targets in dystonia based on recent preclinical animal studies and clinical trials investigating novel therapeutics.

Keywords: Anatomy; Animal models; Basal ganglia; Cerebellum; Drug discovery; Therapy.

Figure 1.. Simplified cartoon of basal ganglia-cerebellum anatomical connections.

A. The cartoon depicts a simplified cortico-basal ganglia-thalamo-cortical circuit. Afferents from the cortex and thalamus (left, orange arrows) reach caudate and putamen neuronal populations of cholinergic interneurons (right, green) and projection neurons. Spiny projection neurons give rise to the direct (right, brown) and indirect (right, blue) output pathways, ultimately reaching the basal ganglia output nuclei (globus pallidus externus and substantia nigra pars reticulata), which send the processed information to the thalamus (left, red arrows). The thalamus then project back to the cortex (left, red arrow). B. The cartoon depicts simplified cortico-cerebello-thalamo-cortical connections. Left. The cerebellar cortex has a trilaminar cytoarchitecture composed of the Purkinje cell layer and the molecular layer (green), and of the granular layer (granule cells, red). Parallel fibers (red), originating from granule cells, reach the molecular layer and innervate inhibitory stellate (blue) and basket interneurons, as well as Purkinje cells (green). Purkinje cells are also activated by climbing fibers (blue), which originate in the inferior olive. The pontine nucleus receives cortical afferents and is a source of mossy fibers reaching the contralateral cerebellar cortex (light green arrow). Purkinje cells project to the deep cerebellar nuclei, which in turn convey cerebellar output to the cortex via the thalamus (green arrows). C. Retrograde transneuronal transport of rabies virus in monkeys revealed bidirectional disynaptic connections between the cerebellum and the basal ganglia. Specifically, a pathway originating from the deep cerebellar nuclei and reaching the putamen (blue arrows; Hoshi et al., 2005), and a pathway connecting the subthalamic nucleus to the cerebellar cortex (light blue arrows; Bostan et al., 2010) were identified.