Circuit failures in primary dystonia: cells, synapses, and behaviour (360G-Wellcome-227433_Z_23_Z)

Dystonia is a common movement disorder, but its pathophysiological mechanisms are poorly understood. Currently, there is no cure, with treatments focussed on symptom management. The development of novel, targeted treatment strategies will require new foundational knowledge of the pathophysiology of this neural circuit disorder. By using mouse genetics, we recently showed that spinal cord circuit dysfunction underlies the pathophysiology of the most common genetic dystonia. In this ambitious proposal, we will leverage this new knowledge, proposing to dissect the pathological neural substrates to determine how their specific dysfunction - from cells to synapses - contributes to the movement disorder. We will confine the genetic manipulations to four key components of motor control: motoneurons, sensory afferents, spinal inhibitory circuits, and myelin, with the goal of dissecting the mechanisms by which each of these elements contribute to dystonic phenotypes. We will then generate a new mouse with the human Tor1a gene (and conditional dystonia mutation), in order to match more closely the human condition. By the completion of the eight year term of this programme, we will have a solid understanding of the cellular and circuit pathophysiology of dystonia, paving the way for new treatment possibilities.