Mouse Models of Dystonia

Hess, Ellen J.; Jinnah, H. A.

doi:10.1016/b978-0-12-405195-9.00027-5

Cited by 5 publications

(3 citation statements)

References 167 publications

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“…Studies in both human patients (5) and rodent models (9) have suggested that the cerebellum plays a key role in the onset and regulation of dystonia. Indeed, genetic, molecular, and pharmacological manipulation of cerebellar activity in several animal models has been shown to cause robust and severe dystonic phenotypes (9)(10)(11)(12). Among these phenotypes are the altered muscle contractions and consequent abnormal movements such as twisting postures, hyper-extended limbs, and tremor.…”

Section: Introductionmentioning

confidence: 99%

Potential Interactions Between Cerebellar Dysfunction and Sleep Disturbances in Dystonia

Leon

Sillitoe²

2022

Dystonia

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Dystonia is the third most common movement disorder. It causes debilitating twisting postures that are accompanied by repetitive and sometimes intermittent co- or over-contractions of agonist and antagonist muscles. Historically diagnosed as a basal ganglia disorder, dystonia is increasingly considered a network disorder involving various brain regions including the cerebellum. In certain etiologies of dystonia, aberrant motor activity is generated in the cerebellum and the abnormal signals then propagate through a “dystonia circuit” that includes the thalamus, basal ganglia, and cerebral cortex. Importantly, it has been reported that non-motor defects can accompany the motor symptoms; while their severity is not always correlated, it is hypothesized that common pathways may nevertheless be disrupted. In particular, circadian dysfunction and disordered sleep are common non-motor patient complaints in dystonia. Given recent evidence suggesting that the cerebellum contains a circadian oscillator, displays sleep-stage-specific neuronal activity, and sends robust long-range projections to several subcortical regions involved in circadian rhythm regulation, disordered sleep in dystonia may result from cerebellum-mediated dysfunction of the dystonia circuit. Here, we review the evidence linking dystonia, cerebellar network dysfunction, and cerebellar involvement in sleep. Together, these ideas may form the basis for the development of improved pharmacological and surgical interventions that could take advantage of cerebellar circuitry to restore normal motor function as well as non-motor (sleep) behaviors in dystonia.

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Section: Introductionmentioning

confidence: 99%

Potential Interactions Between Cerebellar Dysfunction and Sleep Disturbances in Dystonia

Leon

Sillitoe²

2022

Dystonia

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“…Genetic models can duplicate human diseases and are good for understanding their mechanism, although they are complicated regarding nervous system diseases. The drug-induced dystonia model mouse is easy and useful for establishing dystonia pathophysiologically, although these mice do not exactly reflect patient conditions ( Hess and Jinnah, 2015 ). In this study, we used Calderon's model ( Calderon et al, 2011 ) to examine the influence of cerebellar abnormalities on basal ganglia circuitry and investigate its pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

Striatal parvalbumin interneurons are activated in a mouse model of cerebellar dystonia

Matsuda,

Morigaki,

Hayasawa

et al. 2024

Disease Models &Amp; Mechanisms

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Dystonia is supposed to arise from abnormalities in the motor loop of the basal ganglia; however, there is an ongoing debate regarding cerebellar involvement. We adopted the established cerebellar dystonia mice model by injecting ouabain to examine the contribution of the cerebellum. Initially, we examined whether the entopeduncular nucleus (EPN), substantia nigra pars reticulata (SNr), globus pallidus externus (GPe), and striatal neurons were activated in the model. Next, we examined whether dopamine D1 receptor agonists (D1 agonist) and dopamine D2 receptor antagonists (D2 antagonist) or selective ablation of striatal parvalbumin (PV) interneurons could modulate their involuntary movements. The cerebellar dystonia mice had a higher number of c-fos-positive cells in the EPN, SNr, and GPe, as well as a higher positive ratio of c-fos in striatal PV interneurons than the control mice. Furthermore, systemic administration of combined D1 agonist and D2 antagonist and selective ablation of striatal PV interneurons relieved their involuntary movements. Abnormalities in the motor loop of the basal ganglia could be crucially involved in cerebellar dystonia, and modulating PV interneurons might provide a novel treatment strategy.

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“…This is, in part, due to the heterogeneity in the etiology, manifestation, and comorbidity of dystonia symptoms with other movement disorders including ataxia and tremor [7][8][9][10][11][12][13]. Further, few genetic mouse models of primary dystonia recapitulate the behavioral aspects of the human disease [14][15][16], although viral-, pharmacological-, and circuit-based mouse models do show overt dystonic movements and relevant abnormal postures [16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Cerebellar dysfunction in rodent models with dystonia, tremor, and ataxia

van der Heijden,

Sillitoe

2023

Dystonia

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Dystonia is a movement disorder characterized by involuntary co- or over-contractions of the muscles, which results in abnormal postures and movements. These symptoms arise from the pathophysiology of a brain-wide dystonia network. There is mounting evidence suggesting that the cerebellum is a central node in this network. For example, manipulations that target the cerebellum cause dystonic symptoms in mice, and cerebellar neuromodulation reduces these symptoms. Although numerous findings provide insight into dystonia pathophysiology, they also raise further questions. Namely, how does cerebellar pathophysiology cause the diverse motor abnormalities in dystonia, tremor, and ataxia? Here, we describe recent work in rodents showing that distinct cerebellar circuit abnormalities could define different disorders and we discuss potential mechanisms that determine the behavioral presentation of cerebellar diseases.

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Mouse Models of Dystonia

Cited by 5 publications

References 167 publications

Potential Interactions Between Cerebellar Dysfunction and Sleep Disturbances in Dystonia

Potential Interactions Between Cerebellar Dysfunction and Sleep Disturbances in Dystonia

Striatal parvalbumin interneurons are activated in a mouse model of cerebellar dystonia

Cerebellar dysfunction in rodent models with dystonia, tremor, and ataxia

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