Heterozygous Gnal Mice Are a Novel Animal Model with Which to Study Dystonia Pathophysiology
| العنوان: | Heterozygous Gnal Mice Are a Novel Animal Model with Which to Study Dystonia Pathophysiology |
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| المؤلفون: | Fabien Menardy, Jean-Antoine Girault, Daniela Popa, Assunta Pelosi, Denis Hervé |
| المساهمون: | Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ANR-16-CE37-0003,AMEDYST,Altération des réseaux moteurs dans la dystonie primaire(2016) |
| المصدر: | Journal of Neuroscience Journal of Neuroscience, 2017, 37 (26), pp.6253-6267. ⟨10.1523/JNEUROSCI.1529-16.2017⟩ |
| بيانات النشر: | HAL CCSD, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, medicine.medical_specialty, Heterozygote, G-protein, Movement, striatum, [SDV]Life Sciences [q-bio], Mice, Transgenic, Striatum, muscarinic drugs, 03 medical and health sciences, Mice, 0302 clinical medicine, Dopamine, Internal medicine, cAMP, Mecamylamine, medicine, Oxotremorine, Animals, Research Articles, Dystonia, Mice, Knockout, General Neuroscience, Brain, medicine.disease, Pirenzepine, genetic mouse model, GTP-Binding Protein alpha Subunits, Motor coordination, cAMP dystonia G-protein genetic mouse model muscarinic drugs striatum, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Endocrinology, Cholinergic, Female, dystonia, Psychology, Neuroscience, 030217 neurology & neurosurgery, medicine.drug |
| الوصف: | 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, Gα(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(+/−)) 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-CaMKIIβ in the striatum. After systemic administration of oxotremorine, an unselective cholinergic agonist, Gnal(+/−) 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(+/−) 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(+/−) mice provide a model of presymptomic and symptomatic stages of DYT25-associated dystonia, respectively, and clues about the mechanisms underlying dystonia pathogenesis. SIGNIFICANCE STATEMENT Adult-onset dystonia DYT25 is caused by dominant loss-of-function mutations of GNAL, a gene encoding the stimulatory G-protein Gαolf, which is critical for activation of the cAMP pathway in the striatal projection neurons. Here, we demonstrate that Gnal-haplodeficient mice have a mild neurological phenotype and display vulnerability to developing dystonic movements after systemic or intrastriatal injection of the cholinergic agonist oxotremorine. Therefore, impairment of the cAMP pathway in association with an increased cholinergic tone creates alterations in striatal neuron functions that can promote the onset of dystonia. Our results also provide evidence that untreated and oxotremorine-treated Gnal-haplodeficient mice are powerful models with which to study presymptomic and symptomatic stages of DYT25-associated dystonia, respectively. |
| اللغة: | English |
| تدمد: | 0270-6474 1529-2401 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a23110f9233a7fe1fb687c1efd4f2809Test https://hal.science/hal-03983794Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a23110f9233a7fe1fb687c1efd4f2809 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 02706474 15292401 |
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