Heterozygous Gnal Mice Are a Novel Animal Model with Which to Study Dystonia Pathophysiology

Abstract

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions and its pathophysiological mechanisms are still poorly understood. Dominant mutations of the GNAL gene are a cause of isolated dystonia (DYT25) in patients. Some mutations result in a complete loss of function of the encoded protein, G␣ olf , an adenylyl-cyclase-stimulatory G-protein highly enriched in striatal projection neurons, where it mediates the actions of dopamine and adenosine. We used male and female heterozygous Gnal knock-out mice (Gnal ϩ/ Ϫ ) to study how GNAL haplodeficiency is implicated in dystonia. In basal conditions, no overt dystonic movements or postures or change in locomotor activity were observed. However, Gnal haploinsufficiency altered self-grooming, motor coordination, and apparent motivation in operant conditioning, as well as spine morphology and phospho-CaMKII␤ in the striatum. After systemic administration of oxotremorine, an unselective cholinergic agonist, Gnal ϩ/ Ϫ mice developed more abnormal postures and movements than WT mice. These effects were not caused by seizures as indicated by EEG recordings. They were prevented by the M1-preferring muscarinic antagonists, telenzepine, pirenzepine, and trihexyphenidyl, which alleviate dystonic symptoms in patients. The motor defects were worsened by mecamylamine, a selective nicotinic antagonist. These oxotremorine-induced abnormalities in Gnal ϩ/ Ϫ mice were replicated by oxotremorine infusion into the striatum, but not into the cerebellum, indicating that defects in striatal neurons favor the appearance of dystonia-like movement alterations after oxotremorine. Untreated and oxotremorine-treated Gnal ϩ/ Ϫ mice provide a model of presymptomic and symptomatic stages of DYT25-associated dystonia, respectively, and clues about the mechanisms underlying dystonia pathogenesis.

Quantitative trait locus mapping and analysis of heritable variation in affiliative social behavior and co‐occurring traits

“…Gnal is cis‐regulated, possesses a nonsynonymous coding variant between the parental strains, and is expressed in sensory neurons of the olfactory epithelium and at high levels in the olfactory tubercle, striatum, hippocampus and cerebellum . Heterozygous GNAL mutations underlie Dystonia‐25 in humans and a similar dystonia phenotype in mice . Homozygous null Gnal mutations in mice result in anosmia and high levels of pup mortality because of failure to nurse, with abnormal maternal care exhibited by the rare surviving females .…”

“…95,96 Heterozygous GNAL mutations underlie Dystonia-25 97 in humans and a similar dystonia phenotype in mice. 98 Homozygous null…”

Roles of the M4 acetylcholine receptor in the basal ganglia and the treatment of movement disorders

“…Interestingly, possibly because of the common pathophysiological changes induced by low DA in PD and disturbances in the dopaminergic system in some dystonia patients, up to 40% of PD patients also have a comorbidity of dystonia . GNAL mutations associated with dystonia are believed to be loss‐of‐function mutations, and initial animal studies modeling mutations in GNAL indicate that the loss of Gα olf can lead to decreased motor coordination and to evoked dystonic‐like movements . Recent findings from our laboratory that M 4 directly and tonically inhibits D 1 DR/Gα olf signaling is interesting given the recent genetic studies showing that mutations in GNAL are a major cause of adult onset primary dystonia .…”

“…83,84 GNAL mutations associated with dystonia are believed to be loss-of-function mutations, 80 and initial animal studies modeling mutations in GNAL indicate that the loss of Gα olf can lead to decreased motor coordination and to evoked dystonic-like movements. 85 Recent findings from our laboratory that M 4 directly and tonically inhibits D 1 DR/Gα olf signaling is interesting given the recent genetic studies showing that mutations in GNAL are a major cause of adult onset primary dystonia. 9,80 This suggests that the loss of function in Gα olf induced by mutations in GNAL may allow tonic inhibition of D 1 DR/Gα olf by M 4 to predominate and possibly lead to or exacerbate dystonic motor phenotypes.…”

Functional abnormalities in the cerebello-thalamic pathways in an animal model of dystonia

“…Structural defects in the cerebello-thalamo-cortical pathway have been 72 identified in a mouse model of DYT1 dystonia (Ulug et al, 2011), but they have been proposed to 73 provide a protective effect and limit the penetrance of the disease in patients (Argyelan et al, 2009), 74 consistent with the view that dystonias are brain motor network disorders, where dysfunction of one 75 node results in dysfunctions/adaptations in the others. (Pelosi et al, 2017). Gnal haplo-deficiency reduces striatal cAMP production and disrupts 82 striatal functions but the mice are asymptomatic in terms of dystonia.…”