Functional abnormalities in the cerebellothalamic pathways in a mouse model of DYT25 dystonia

Dystonia is often associated with functional alterations in the cerebello-thalamic pathways, which have been proposed to contribute to the disorder by propagating pathological firing patterns to the forebrain. Here, we examined the function of the cerebello-thalamic pathways in a model of DYT25 dystonia. DYT25 (Gnal+/−) mice carry a heterozygous knockout mutation of the Gnal gene, which notably disrupts striatal function, and systemic or striatal administration of oxotremorine to these mice triggers dystonic symptoms. Our results reveal an increased cerebello-thalamic excitability in the presymptomatic state. Following the first dystonic episode, Gnal+/- mice in the asymptomatic state exhibit a further increase of the cerebello-thalamo-cortical excitability, which is maintained after θ-burst stimulations of the cerebellum. When administered in the symptomatic state induced by a cholinergic activation, these stimulations decreased the cerebello-thalamic excitability and reduced dystonic symptoms. In agreement with dystonia being a multiregional circuit disorder, our results suggest that the increased cerebello-thalamic excitability constitutes an early endophenotype, and that the cerebellum is a gateway for corrective therapies via the depression of cerebello-thalamic pathways.Fil: Aïssa, Hind Baba. Ecole Normale Supérieure; FranciaFil: Sala, Romain W.. Ecole Normale Supérieure; FranciaFil: Georgescu Margarint, Elena Laura. Ecole Normale Supérieure; FranciaFil: Frontera, Jimena Laura. Ecole Normale Supérieure; FranciaFil: Varani, Andrés Pablo. Ecole Normale Supérieure; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Menardy, Fabien. Ecole Normale Supérieure; FranciaFil: Pelosi, Assunta. Inserm; Francia. Université Pierre et Marie Curie; FranciaFil: Hervé, Denis. Université Pierre et Marie Curie; Francia. Inserm; Francia. Institut Du Fer À Moulin; FranciaFil: Léna, Clément. Ecole Normale Supérieure; FranciaFil: Popa, Daniela. Ecole Normale Supérieure; Franci

Defined neuronal populations drive fatal phenotype in a mouse model of leigh syndrome

Altres ajuts: Seattle Children's Research Institute: Seed Funds;NINDS: R01 NIH/NS 102796; University of Washington Neurological Surgery Department: Ellenbogen Neurological Surgery Research Funds; University of Washington: The Ryan J. Murphy SUDEP Research Funds; Mitochondrial Research Guild: Seed FundsMitochondrial deficits in energy production cause untreatable and fatal pathologies known as mitochondrial disease (MD). Central nervous system affectation is critical in Leigh Syndrome (LS), a common MD presentation, leading to motor and respiratory deficits, seizures and premature death. However, only specific neuronal populations are affected. Furthermore, their molecular identity and their contribution to the disease remains unknown. Here, using a mouse model of LS lacking the mitochondrial complex I subunit Ndufs4, we dissect the critical role of genetically-defined neuronal populations in LS progression. Ndufs4 inactivation in Vglut2expressing glutamatergic neurons leads to decreased neuronal firing, brainstem inflammation, motor and respiratory deficits, and early death. In contrast, Ndufs4 deletion in GABAergic neurons causes basal ganglia inflammation without motor or respiratory involvement, but accompanied by hypothermia and severe epileptic seizures preceding death. These results provide novel insight in the cell type-specific contribution to the pathology, dissecting the underlying cellular mechanisms of MD