How relevant is the cholinergic system in DYT1 dystonia?

Work over the past decades revealed a relevant role for striatal cholinergic interneurons in the context of basal ganglia function and dysfunction. Loss of the reciprocal modulation between striatal dopamine and acetylcholine appears to be the primary event for pathophysiological changes occurring in distinct basal ganglia disorders, such as dystonia. There is now robust evidence to suggest that cholinergic interneuron activity is profoundly affected in dystonia. This seems to be caused by an altered dopaminergic control of cholinergic function, but also partly determined by intrinsic cholinergic defects. Several forms of primary dystonia are commonly treated with broad-spectrum antimuscarinic drugs, although this approach is not devoid of serious side effects. Thus, it is essential to improve our understanding of the underlying cholinergic mechanisms in order to seek improved therapies. The identification of the involvement of striatal interneurons in synaptic plasticity and motor learning represents a significant advance in the comprehension of how the striatum processes cortical inputs, and how network distortion may generate motor dysfunction. Here, we provide an overview of the role of striatal cholinergic transmission in the context of the pathogenesis of dystonia.