Pathophysiology of Dyt1- Tor1a dystonia in mice is mediated by spinal neural circuit dysfunction

Abstract

Dystonia, a neurological disorder defined by abnormal postures and disorganized movements, is considered to be a neural circuit disorder with dysfunction arising within and between multiple brain regions. Given that spinal neural circuits constitute the final pathway for motor control, we sought to determine their contribution to this movement disorder. Focusing on the most common inherited form of dystonia in humans, DYT1- TOR1A , we generated a conditional knockout of the torsin family 1 member A ( Tor1a ) gene in the mouse spinal cord and dorsal root ganglia (DRG). We found that these mice recapitulated the phenotype of the human condition, developing early-onset generalized torsional dystonia. Motor signs emerged early in the mouse hindlimbs before spreading caudo-rostrally to affect the pelvis, trunk, and forelimbs throughout postnatal maturation. Physiologically, these mice bore the hallmark features of dystonia, including spontaneous contractions at rest and excessive and disorganized contractions, including cocontractions of antagonist muscle groups, during voluntary movements. Spontaneous activity, disorganized motor output, and impaired monosynaptic reflexes, all signs of human dystonia, were recorded from isolated mouse spinal cords from these conditional knockout mice. All components of the monosynaptic reflex arc were affected, including motor neurons. Given that confining the Tor1a conditional knockout to DRG did not lead to early-onset dystonia, we conclude that the pathophysiological substrate of this mouse model of dystonia lies in spinal neural circuits. Together, these data provide new insights into our current understanding of dystonia pathophysiology.

Spinal Dystonia Associated with Transverse Myelitis in an Adolescent Female: A Case Report

“…2 , 3 A recent study on mice to determine the role of spinal cord in spinal-generated movement disorder also supports the major role played by the spinal cord in dystonia. 4 …”

MRI-Guided Focused Ultrasound for the Treatment of Dystonia: A Narrative Review

“…Classically, the underlying pathophysiology of dystonia has been considered to occur secondary to basal ganglia dysfunction, such as other movement disorders, centered on reports of dystonic syndromes arising from lesions involving the basal ganglia [8]. However, recent theories purport a "circuitopathy" affecting multiple anatomical regions connected by the basal ganglia-cerebello-thalamo-cortical circuits, based on the observation that functional neuroimaging studies do not demonstrate abnormalities in discrete brain regions in dystonia patients [1,9,10]. Interestingly, a recent preclinical study by the Brownstone group showed that spinal circuit dysfunction alone was sufficient to cause dystonic-like features in a Dyt- Tor1a mouse model [10].…”

“…However, recent theories purport a "circuitopathy" affecting multiple anatomical regions connected by the basal ganglia-cerebello-thalamo-cortical circuits, based on the observation that functional neuroimaging studies do not demonstrate abnormalities in discrete brain regions in dystonia patients [1,9,10]. Interestingly, a recent preclinical study by the Brownstone group showed that spinal circuit dysfunction alone was sufficient to cause dystonic-like features in a Dyt- Tor1a mouse model [10].…”

Chronic striatal cholinergic interneuron excitation induces clinically-relevant dystonic behavior in mice

“…(30)(31)(32) Electromyographic measures of antagonist muscle co-contraction have also been used to quantify dystonia in rodents. (19,33,34). However, antagonist muscle co-contraction is not specific to dystonia alone and can be seen associated with other motor symptoms like spasticity, (35,36) which often co-occurs with dystonia and requires a different treatment paradigm.…”