Cell-specific effects of Dyt1 knock-out on sensory processing, network-level connectivity, and motor deficits

Exp Neurol. 2021 Sep;343:113783. doi: 10.1016/j.expneurol.2021.113783. Epub 2021 Jun 10.


DYT1 dystonia is a debilitating movement disorder characterized by repetitive, unintentional movements and postures. The disorder has been linked to mutation of the TOR1A/DYT1 gene encoding torsinA. Convergent evidence from studies in humans and animal models suggest that striatal medium spiny neurons and cholinergic neurons are important in DYT1 dystonia. What is not known is how torsinA dysfunction in these specific cell types contributes to the pathophysiology of DYT1 dystonia. In this study we sought to determine whether torsinA dysfunction in cholinergic neurons alone is sufficient to generate the sensorimotor dysfunction and brain changes associated with dystonia, or if torsinA dysfunction in a broader subset of cell types is needed. We generated two genetically modified mouse models, one with selective Dyt1 knock-out from dopamine-2 receptor expressing neurons (D2KO) and one where only cholinergic neurons are impacted (Ch2KO). We assessed motor deficits and performed in vivo 11.1 T functional MRI to assess sensory-evoked brain activation and connectivity, along with diffusion MRI to assess brain microstructure. We found that D2KO mice showed greater impairment than Ch2KO mice, including reduced sensory-evoked brain activity in key regions of the sensorimotor network, and altered functional connectivity of the striatum that correlated with motor deficits. These findings suggest that (1) the added impact of torsinA dysfunction in medium spiny and dopaminergic neurons of the basal ganglia generate more profound deficits than the dysfunction of cholinergic neurons alone, and (2) that sensory network impairments are linked to motor deficits in DYT1 dystonia.

Keywords: Basal ganglia; Cholinergic neurons; Cortex; Diffusion MRI; Dopamine-2 receptor; Dystonia; Dyt1; Functional MRI; Sensorimotor; torsinA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • Dystonia Musculorum Deformans / diagnostic imaging
  • Dystonia Musculorum Deformans / genetics
  • Dystonia Musculorum Deformans / metabolism*
  • Gene Knockdown Techniques / methods
  • Locomotion / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Nerve Net / diagnostic imaging
  • Nerve Net / metabolism*


  • Dyt1 protein, mouse
  • Molecular Chaperones

Supplementary concepts

  • Dystonia musculorum deformans type 1