implantation-osmotic-pumps-induction-stress-to-establish-symptomatic

Implantation of Osmotic Pumps and Induction of Stress to Establish a Symptomatic, Pharmacological Mouse Model for DYT/PARK-ATP1A3 Dystonia

Genetically modified mouse models face limitations, especially when studying movement disorders, where most of the available transgenic rodent models do ...

multifactorial-assessment-motor-behavior-rats-after-unilateral

Multifactorial Assessment of Motor Behavior in Rats after Unilateral Sciatic Nerve Crush Injury

The induction of a peripheral nerve injury is a widely used method in neuroscience for the assessment of repair and pain mechanisms among others. In ...

University Hospital of Würzburg

Rapid-onset dystonia-parkinsonism (RDP) is a rare form of hereditary dystonia caused by loss-of-function mutations of the Na/K-ATPase α3 isoform (ATP1α3). An acute onset of generalized dystonia and parkinsonism after exposure to stress and an incomplete disease penetrance is described in RDP, thereby suggesting a gene-environmental interaction in individuals with a genetic predisposition for dystonia development. Dystonia is considered a central motor network disease and in line with this concept, alterations in cerebellar neuronal firing have been described in RDP mouse models, but the pathogenic role of the basal ganglia remains unclear. We have mimicked RDP pharmacologically by simultaneous perfusion of the selective ATP1α3-blocker ouabain into the striatum and cerebellum of mice, followed by repeated exposure to mild motor stress. Ouabain-perfused RDP mice developed dystonia-like movements, which were exacerbated by exposure to sensorimotor stress. Compared to control mice, ouabain perfusion of the striatum led to dendritic spine loss of medium spiny neurons in addition to loss of cholinergic and GABAergic interneurons in the striatum. High-pressure liquid chromatography analyses revealed significant dopamine (DA) depletion and increased DA and serotonergic turnover, while qPCR analyses displayed reduction of glutamatergic receptors. Adding stress to the ouabain-predisposed brain, however, resulted in an elevation of the striatal DA metabolism back to the level of control animals. Our results indicate an ouabain-induced basal ganglia and cerebellar motor network dysfunction characterized by structural and neurochemical alterations of striatal dopaminergic, cholinergic and glutamatergic pathways that represent a motor endophenotype of RDP mutation carriers. Challenging the motor circuit by sensorimotor stress causes exacerbation of dystonia-like movements tightly linked to a hyperdopaminergic state in the striatum. Our observations support a gene-environment interaction or "second-hit" hypothesis in the symptomatogenesis of RDP.

Striatal dopaminergic dysregulation and dystonia-like movements induced by sensorimotor stress in a pharmacological mouse model of rapid-onset dystonia-parkinsonism.

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.

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.

Lisa Rauschenberger

Department of Neurology

University Hospital of Würzburg

Implantation of Osmotic Pumps and Induction of Stress to Establish a Symptomatic, Pharmacological Mouse Model for DYT/PARK-ATP1A3 Dystonia

Multifactorial Assessment of Motor Behavior in Rats after Unilateral Sciatic Nerve Crush Injury