Animal models of generalized dystonia

Abstract

Summary: Dystonia is a prevalent neurological disorder characterized by abnormal co-contractions of antagonistic muscle groups that produce twisting movements and abnormal postures. The disorder may be inherited, arise sporadically, or result from brain insult. Dystonia is a heterogeneous disorder because patients may exhibit focal or generalized symptoms associated with abnormalities in many brain regions including basal ganglia and cerebellum. Elucidating the pathogenic mechanisms underlying dystonia has therefore been challenging. Animal models of dystonia exhibit similar heterogeneity and are useful for understanding pathogenesis. The neurochemical and neurophysiological abnormalities in rodents with idiopathic generalized dystonia suggest that dysfunctional output from basal ganglia, cerebellum, or from multiple systems is the cause of motor dysfunction. Findings from drug-or toxininduced dystonia in rodents and nonhuman primates mirror the genetic models. The parallels between dystonia in humans and animals suggest that the models will continue to prove useful in determining pathogenesis. Furthermore, detailed characterization of the existing models of dystonia and the development of new models hold promise for the identification of novel therapeutics.

Dystonia Pathophysiology: A Critical Review

“…The cellular mechanisms leading to a dysfunctionning of the cerebellum remains less clear but some observations in rodent models suggest a possible dysfunctionning of Purkinje cells potentially related to some forms of channelopathy (11). Thus, animal models are promising although none of them can perfectly mimic the complexity of the clinical features observed in humans (1,12). A problem in the genotypic rodent models is that they do not induce a phenotypic of dystonia.…”

“…In phenotypic models, mutations that produce dystonic movements occur naturally (12). The dt/dt rat has an autosomal, recessive condition with dystonic posturing appearing 10 days after birth encompassing twisting movements of the neck, padding motions of the limbs and postural instability of increasing severity (71).…”

“…At the most advanced stages of attacks, tottering mice assume prolonged twisting postures involving the whole body and a mild ataxia. Lethargic mice also exhibit paroxysmal dyskinesia triggered by procedures that promote motor activity (12). In these animals, cytochrome oxydase histochemistry revealed increased activity in the red nucleus.…”

“…Thus, lesions of the cerebellum in rodents models of dystonia abolish the motor disorder suggesting that the cerebellum is necessary for the expression of dystonia (12). Morevover, it was shown in the dt rat that abnormal signaling in cerebellar cortex can lead to abnormal cerebellar output (11,74).…”

“…Several excellent reviews have been recently proposed on this topic (2)(3)(4)(5)(6)(7)(8). Moreover, animals models of dystonia can help us to investigate the pathogenesis since they provide the opportunity to dissect more precisely the abnormal neuronal networks leading to primary dystonia and its genetic background (9)(10)(11)(12).…”