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Cell-specific effects of Dyt1 knock-out on sensory processing, network-level connectivity, and motor deficits
B J Wilkes1, J C DeSimone1, Y Liu2
1Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA.
Experimental Neurology
|June 13, 2021
Summary
DYT1 dystonia involves torsinA gene mutations. This study found that dysfunction in medium spiny and dopaminergic neurons, not just cholinergic neurons, causes more severe sensorimotor deficits and brain changes in mouse models.
Area of Science:
- Neuroscience
- Genetics
- Movement Disorders
Background:
- DYT1 dystonia is a movement disorder linked to the TOR1A/DYT1 gene mutation affecting torsinA.
- Striatal medium spiny neurons and cholinergic neurons are implicated, but the precise cellular mechanisms remain unclear.
Purpose of the Study:
- To investigate if torsinA dysfunction in cholinergic neurons alone causes dystonia.
- To determine if broader cell type involvement is necessary for dystonia pathophysiology.
Main Methods:
- Generated Dyt1 knockout mouse models: D2KO (dopamine-2 receptor neurons) and Ch2KO (cholinergic neurons).
- Assessed motor deficits.
- Utilized in vivo 11.1T functional MRI for sensory-evoked brain activity and connectivity.
- Employed diffusion MRI for brain microstructure analysis.
Main Results:
- D2KO mice exhibited more significant impairments than Ch2KO mice.
- Reduced sensory-evoked brain activity in sensorimotor networks was observed in D2KO mice.
- Altered striatal functional connectivity correlated with motor deficits.
Conclusions:
- TorsinA dysfunction in medium spiny and dopaminergic neurons contributes more significantly to DYT1 dystonia deficits than cholinergic neuron dysfunction alone.
- Impaired sensory networks are associated with motor deficits in DYT1 dystonia.
