Altered Functional Brain Connectivity in Dyt1 Knock-in mouse models.

Area of Science:

• Neuroscience
• Genetics
• Systems Biology

Background:

• DYT1 dystonia is a hereditary movement disorder caused by a DYT1 gene mutation affecting TorsinA protein.
• Dystonia is increasingly viewed as a functional network disorder, but the role of TorsinA dysfunction in specific cell types on network connectivity is unclear.

Purpose of the Study:

• To investigate the impact of global versus cortex-specific TorsinA dysfunction on brain network connectivity in DYT1 dystonia.
• To elucidate how TorsinA mutations affect pathophysiology in distinct neuronal populations.

Main Methods:

• Generated two mouse models: global Dyt1 dGAG knock-in (dGAG) and cortex-specific Dyt1 dGAG knock-in (EMX).
• Utilized ultra-high field 11.1T in vivo neuroimaging, including functional MRI (fMRI) for connectivity and diffusion MRI (dMRI) for microstructure.
• Assessed resting-state and sensory-evoked brain connectivity and activation patterns.

Main Results:

• Global TorsinA dysfunction (dGAG mice) led to reduced functional connectivity in sensorimotor networks, including globus pallidus, somatosensory cortex, thalamus, and cerebellum.
• Cortex-specific TorsinA dysfunction (EMX mice) showed altered connectivity between the cerebellum, striatum, and brainstem.
• Both models demonstrated functional connectivity alterations involving the basal ganglia and cerebellum, underscoring the cerebellum's role in dystonia.

Conclusions:

• DYT1 dystonia is a network disorder where TorsinA dysfunction in various neuronal types contributes to pathophysiology.
• Cerebellar involvement is critical in dystonia, even with localized TorsinA dysfunction.
• Therapeutic strategies for dystonia may benefit from targeting network properties across multiple brain regions.