Unraveling the neural substrates of Rapid Onset Dystonia Parkinsonism

Abstract

Rapid Onset Dystonia Parkinsonism (RDP) is an inherited autosomal dominant movement disorder characterized by the rapid onset of combined dystonia and parkinsonism. The symptoms include limb and cranial dystonic spasms, bradykinesia, slow gait, dysarthria and postural instability which appear rapidly over hours to weeks after severe stress. The disease is caused by mutations in the alpha3 isoform of the Na/K ATPase, which reduce the sodium pump's activity. Even though the genetic basis of this disorder is known, it is currently unclear how dysfunction of the sodium pump results in RDP. Furthermore, the anatomical brain structures that malfunction in this disease have not been identified. To date, genetic manipulations have failed to reproduce human dystonia in mice. Thus, we took advantage of ouabain, a potent and exquisitely selective blocker of sodium pumps, to generate a pharmacological animal model of RDP. We found that chronic in vivo perfusion of ouabain into the basal ganglia of mice generated severe parkinsonism-like symptoms. Blockade of sodium pumps in the basal ganglia, however, never produced dystonia. Chronic perfusion of ouabain into the cerebellum, in contrast, resulted in ataxia and severe dystonic episodes.;In addition, human subjects affected with the mutated RDP gene show few symptoms prior to the sudden onset of the disease which is triggered by an extremely stressful experience. Concurrent perfusion of both the basal ganglia and the cerebellum with sub-threshold concentrations of ouabain in mice caused mild symptoms which resembled those seen in human subjects prior to the onset of RDP. Moreover, exposing these animals to an episode of severe stress resulted in pronounced and permanent dystonia. The same stress did not generate any motor symptoms if either the cerebellum or the basal ganglia alone were perfused with ouabain.;Several lines of evidence suggest that abnormal cerebellar activity can cause dystonia. We examined the possibility that ouahain-induced dystonia was caused by aberrant cerebellar activity by performing EEGs in the cerebellum. These experiments revealed that dysfunction of sodium pumps causes cerebellar hyperactivity. These data thus suggest an adverse interaction between the basal ganglia and Cerebellum and point to cerebellar hyperactivity as a potential correlate of dystonia in RDP.