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Neurobiol Dis. 2017 Oct;106:124-132. doi: 10.1016/j.nbd.2017.06.015. Epub 2017 Jul 1.

Forebrain knock-out of torsinA reduces striatal free-water and impairs whole-brain functional connectivity in a symptomatic mouse model of DYT1 dystonia.

Author information

1
Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611, USA.
2
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
3
Department of Psychiatry, College of Medicine, University of Florida, Gainesville, FL 32611, USA.
4
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA; Veteran Affairs Ann Arbor Healthcare System, University of Michigan, Ann Arbor, MI 48105, USA.
5
Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611, USA; Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA. Electronic address: vcourt@ufl.edu.

Abstract

Multiple lines of evidence implicate striatal dysfunction in the pathogenesis of dystonia, including in DYT1, a common inherited form of the disease. The impact of striatal dysfunction on connected motor circuits and their interaction with other brain regions is poorly understood. Conditional knock-out (cKO) of the DYT1 protein torsinA from forebrain cholinergic and GABAergic neurons creates a symptomatic model that recapitulates many characteristics of DYT1 dystonia, including the developmental onset of overt twisting movements that are responsive to antimuscarinic drugs. We performed diffusion MRI and resting-state functional MRI on cKO mice of either sex to define abnormalities of diffusivity and functional connectivity in cortical, subcortical, and cerebellar networks. The striatum was the only region to exhibit an abnormality of diffusivity, indicating a selective microstructural deficit in cKO mice. The striatum of cKO mice exhibited widespread increases in functional connectivity with somatosensory cortex, thalamus, vermis, cerebellar cortex and nuclei, and brainstem. The current study provides the first in vivo support that direct pathological insult to forebrain torsinA in a symptomatic mouse model of DYT1 dystonia can engage genetically normal hindbrain regions into an aberrant connectivity network. These findings have important implications for the assignment of a causative region in CNS disease.

KEYWORDS:

DYT1 dystonia; Diffusion MRI; Free-water; Functional MRI; Functional connectivity; Mouse model

PMID:
28673740
PMCID:
PMC5555738
DOI:
10.1016/j.nbd.2017.06.015
[Indexed for MEDLINE]
Free PMC Article

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