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

Elena Laura Margarint, Hind Baba Aïssa, Andrés Pablo Varani, Romain Sala, View ORCID ProfileFabien Menardy, Assunta Pelosi, View ORCID ProfileDenis Hervé, View ORCID ProfileClément Léna, View ORCID ProfileDaniela Popa
doi: https://doi.org/10.1101/2020.01.29.926170
Elena Laura Margarint
1Neurophysiology of Brain Circuits Team, Institut de biologie de l’Ecole normale supérieure (IBENS), Ecole normale supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France
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Hind Baba Aïssa
1Neurophysiology of Brain Circuits Team, Institut de biologie de l’Ecole normale supérieure (IBENS), Ecole normale supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France
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Andrés Pablo Varani
1Neurophysiology of Brain Circuits Team, Institut de biologie de l’Ecole normale supérieure (IBENS), Ecole normale supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France
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Romain Sala
1Neurophysiology of Brain Circuits Team, Institut de biologie de l’Ecole normale supérieure (IBENS), Ecole normale supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France
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Fabien Menardy
1Neurophysiology of Brain Circuits Team, Institut de biologie de l’Ecole normale supérieure (IBENS), Ecole normale supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France
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Assunta Pelosi
2Inserm UMR-S 1270, 75005 Paris, France
3Sorbonne Université, Sciences and Technology Faculty, Paris, France
4Institut du Fer à Moulin, 75005 Paris, France
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Denis Hervé
2Inserm UMR-S 1270, 75005 Paris, France
3Sorbonne Université, Sciences and Technology Faculty, Paris, France
4Institut du Fer à Moulin, 75005 Paris, France
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Clément Léna
1Neurophysiology of Brain Circuits Team, Institut de biologie de l’Ecole normale supérieure (IBENS), Ecole normale supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France
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Daniela Popa
1Neurophysiology of Brain Circuits Team, Institut de biologie de l’Ecole normale supérieure (IBENS), Ecole normale supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France
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  • For correspondence: daniela.popa@ens.fr
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ABSTRACT

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, mice carrying a heterozygous invalidation of Gnal gene which notably disrupts striatal function, exhibiting dystonic movements and postures following systemic or striatal administration of oxotremorine. Theta-burst optogenetic stimulations of the cerebellar nuclei evoked a potentiation of the responses to cerebellar stimulations in the thalamus and motor cortex in WT mice, without evident motor function disruption. In contrast, theta burst stimulations evoked a depression of these responses only in dystonia-manifesting Gnal+/− mice after oxotremorine administration, decreased the disabling dystonia attacks, and increased normal active wake behaviour in Gnal+/− mice. The cerebellum could thus offer a gateway for a corrective treatment of motor impairments in dystonia including striatal dysfunction.

One sentence summary A mouse model of DYT25 dystonia, carrying a Gnal mutation disrupting striatal neurotransmission, exhibits anomalous cerebello-thalamic plasticity in the non-manifesting state, but theta-burst cerebellar stimulations during cholinergic-induced dystonia depress the cerebello-thalamic transmission and reduce the severity of the motor symptoms.

Footnotes

  • Data, code and materials availability: The data and the code for electrophysiological analysis will be made available on the team website upon acceptance: https://www.ibens.ens.fr/spip.php?rubrique53&lang=en

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted February 03, 2020.
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Functional abnormalities in the cerebello-thalamic pathways in an animal model of dystonia
Elena Laura Margarint, Hind Baba Aïssa, Andrés Pablo Varani, Romain Sala, Fabien Menardy, Assunta Pelosi, Denis Hervé, Clément Léna, Daniela Popa
bioRxiv 2020.01.29.926170; doi: https://doi.org/10.1101/2020.01.29.926170
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Functional abnormalities in the cerebello-thalamic pathways in an animal model of dystonia
Elena Laura Margarint, Hind Baba Aïssa, Andrés Pablo Varani, Romain Sala, Fabien Menardy, Assunta Pelosi, Denis Hervé, Clément Léna, Daniela Popa
bioRxiv 2020.01.29.926170; doi: https://doi.org/10.1101/2020.01.29.926170

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