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Article dans une revue Journal of Neuroscience Année : 2017

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

Résumé

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 knockout 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.
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hal-03983794, version 1 (11-02-2023)

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Assunta Pelosi, Fabien Menardy, Daniela Popa, Jean-Antoine Girault, Denis Hervé. Heterozygous Gnal Mice Are a Novel Animal Model with Which to Study Dystonia Pathophysiology. Journal of Neuroscience, 2017, 37 (26), pp.6253-6267. ⟨10.1523/JNEUROSCI.1529-16.2017⟩. ⟨hal-03983794⟩
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