The evolution of dystonia-like movements in TOR1A rats after transient nerve injury is accompanied by dopaminergic dysregulation and abnormal oscillatory activity of a central motor network

TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and reduced penetrance of 30–40%. ∆ETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ∆ETorA rat...

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Main Authors: Susanne Knorr, Lisa Rauschenberger, Uri Ramirez Pasos, Maximilian U. Friedrich, Robert L. Peach, Kathrin Grundmann-Hauser, Thomas Ott, Aet O'Leary, Andreas Reif, Philip Tovote, Jens Volkmann, Chi Wang Ip
Format: Article
Language:English
Published: Elsevier 2021-07-01
Series:Neurobiology of Disease
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Online Access:http://www.sciencedirect.com/science/article/pii/S0969996121000863
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author Susanne Knorr
Lisa Rauschenberger
Uri Ramirez Pasos
Maximilian U. Friedrich
Robert L. Peach
Kathrin Grundmann-Hauser
Thomas Ott
Aet O'Leary
Andreas Reif
Philip Tovote
Jens Volkmann
Chi Wang Ip
author_facet Susanne Knorr
Lisa Rauschenberger
Uri Ramirez Pasos
Maximilian U. Friedrich
Robert L. Peach
Kathrin Grundmann-Hauser
Thomas Ott
Aet O'Leary
Andreas Reif
Philip Tovote
Jens Volkmann
Chi Wang Ip
author_sort Susanne Knorr
collection DOAJ
description TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and reduced penetrance of 30–40%. ∆ETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ∆ETorA rats by peripheral nerve injury and to identify central mechanism of dystonia development. Dystonia-like movements (DLM) were assessed using the tail suspension test and implementing a pipeline of deep learning applications. Neuron numbers of striatal parvalbumin+, nNOS+, calretinin+, ChAT+ interneurons and Nissl+ cells were estimated by unbiased stereology. Striatal dopaminergic metabolism was analyzed via in vivo microdialysis, qPCR and western blot. Local field potentials (LFP) were recorded from the central motor network. Deep brain stimulation (DBS) of the entopeduncular nucleus (EP) was performed. Nerve-injured ∆ETorA rats developed long-lasting DLM over 12 weeks. No changes in striatal structure were observed. Dystonic-like ∆ETorA rats presented a higher striatal dopaminergic turnover and stimulus-induced elevation of dopamine efflux compared to the control groups. Higher LFP theta power in the EP of dystonic-like ∆ETorA compared to wt rats was recorded. Chronic EP-DBS over 3 weeks led to improvement of DLM. Our data emphasizes the role of environmental factors in TOR1A symptomatogenesis. LFP analyses indicate that the pathologically enhanced theta power is a physiomarker of DLM. This TOR1A model replicates key features of the human TOR1A pathology on multiple biological levels and is therefore suited for further analysis of dystonia pathomechanism.
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spelling doaj.art-8c06d0bbd2204284a3bf0ac22fbea2a62022-12-21T22:11:31ZengElsevierNeurobiology of Disease1095-953X2021-07-01154105337The evolution of dystonia-like movements in TOR1A rats after transient nerve injury is accompanied by dopaminergic dysregulation and abnormal oscillatory activity of a central motor networkSusanne Knorr0Lisa Rauschenberger1Uri Ramirez Pasos2Maximilian U. Friedrich3Robert L. Peach4Kathrin Grundmann-Hauser5Thomas Ott6Aet O'Leary7Andreas Reif8Philip Tovote9Jens Volkmann10Chi Wang Ip11Department of Neurology, University Hospital of Würzburg, 97080, GermanyDepartment of Neurology, University Hospital of Würzburg, 97080, GermanyDepartment of Neurology, University Hospital of Würzburg, 97080, GermanyDepartment of Neurology, University Hospital of Würzburg, 97080, GermanyDepartment of Neurology, University Hospital of Würzburg, 97080, GermanyInstitute for Medical Genetics and Applied Genomics, University of Tübingen, 72076, Germany; Centre for Rare Diseases, University of Tübingen, 72076, GermanyInstitute for Medical Genetics and Applied Genomics, University of Tübingen, 72076, Germany; Core Facility Transgenic Animals, University Hospital of Tübingen, 72076, GermanyDepartment of Psychiatry, Psychosomatic Medicine, and Psychotherapy, University Hospital Frankfurt, 60528, GermanyDepartment of Psychiatry, Psychosomatic Medicine, and Psychotherapy, University Hospital Frankfurt, 60528, GermanySystems Neurobiology, Institute of Clinical Neurobiology, University Hospital of Würzburg, Versbacher Straße 5, 97080, GermanyDepartment of Neurology, University Hospital of Würzburg, 97080, GermanyDepartment of Neurology, University Hospital of Würzburg, 97080, Germany; Corresponding author at: Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Straße 11, 97080 Würzburg, Germany.TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and reduced penetrance of 30–40%. ∆ETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ∆ETorA rats by peripheral nerve injury and to identify central mechanism of dystonia development. Dystonia-like movements (DLM) were assessed using the tail suspension test and implementing a pipeline of deep learning applications. Neuron numbers of striatal parvalbumin+, nNOS+, calretinin+, ChAT+ interneurons and Nissl+ cells were estimated by unbiased stereology. Striatal dopaminergic metabolism was analyzed via in vivo microdialysis, qPCR and western blot. Local field potentials (LFP) were recorded from the central motor network. Deep brain stimulation (DBS) of the entopeduncular nucleus (EP) was performed. Nerve-injured ∆ETorA rats developed long-lasting DLM over 12 weeks. No changes in striatal structure were observed. Dystonic-like ∆ETorA rats presented a higher striatal dopaminergic turnover and stimulus-induced elevation of dopamine efflux compared to the control groups. Higher LFP theta power in the EP of dystonic-like ∆ETorA compared to wt rats was recorded. Chronic EP-DBS over 3 weeks led to improvement of DLM. Our data emphasizes the role of environmental factors in TOR1A symptomatogenesis. LFP analyses indicate that the pathologically enhanced theta power is a physiomarker of DLM. This TOR1A model replicates key features of the human TOR1A pathology on multiple biological levels and is therefore suited for further analysis of dystonia pathomechanism.http://www.sciencedirect.com/science/article/pii/S0969996121000863DYT1TOR1ATwo-hit hypothesisDopamineLFP
spellingShingle Susanne Knorr
Lisa Rauschenberger
Uri Ramirez Pasos
Maximilian U. Friedrich
Robert L. Peach
Kathrin Grundmann-Hauser
Thomas Ott
Aet O'Leary
Andreas Reif
Philip Tovote
Jens Volkmann
Chi Wang Ip
The evolution of dystonia-like movements in TOR1A rats after transient nerve injury is accompanied by dopaminergic dysregulation and abnormal oscillatory activity of a central motor network
Neurobiology of Disease
DYT1
TOR1A
Two-hit hypothesis
Dopamine
LFP
title The evolution of dystonia-like movements in TOR1A rats after transient nerve injury is accompanied by dopaminergic dysregulation and abnormal oscillatory activity of a central motor network
title_full The evolution of dystonia-like movements in TOR1A rats after transient nerve injury is accompanied by dopaminergic dysregulation and abnormal oscillatory activity of a central motor network
title_fullStr The evolution of dystonia-like movements in TOR1A rats after transient nerve injury is accompanied by dopaminergic dysregulation and abnormal oscillatory activity of a central motor network
title_full_unstemmed The evolution of dystonia-like movements in TOR1A rats after transient nerve injury is accompanied by dopaminergic dysregulation and abnormal oscillatory activity of a central motor network
title_short The evolution of dystonia-like movements in TOR1A rats after transient nerve injury is accompanied by dopaminergic dysregulation and abnormal oscillatory activity of a central motor network
title_sort evolution of dystonia like movements in tor1a rats after transient nerve injury is accompanied by dopaminergic dysregulation and abnormal oscillatory activity of a central motor network
topic DYT1
TOR1A
Two-hit hypothesis
Dopamine
LFP
url http://www.sciencedirect.com/science/article/pii/S0969996121000863
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