Selective and Sustained α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Activation in Cerebellum Induces Dystonia in Mice

Abstract

Dystonia is a neurological disorder characterized by involuntary muscle contractions that cause twisting movements and abnormal postures. Functional imaging consistently reveals cerebellar overactivity in dystonic patients regardless of the type or etiology of the disorder. To explore mechanisms that might explain the basis for the cerebellar overactivity in dystonia, normal mice were challenged with intracerebellar application of a variety of agents that induce hyperexcitability. A nonspecific increase in cerebellar excitability, such as that produced by picrotoxin, was not associated with dystonia. Instead, glutamate receptor activation, specifically AMPA receptor activation, was necessary to evoke dystonia. AMPA receptor agonists induced dystonia, and AMPA receptor antagonists reduced the dystonia induced by glutamate receptor agonists. AMPA receptor antagonists also ameliorated the dystonia exhibited by the dystonic mouse mutant tottering, suggesting that AMPA receptors may play a role in some other genetic models of dystonia. Furthermore, AMPA receptor desensitization mediated the expression of dystonia. Preventing AMPA receptor desensitization with cyclothiazide or the nondesensitizing agonist kainic acid exacerbated the dystonic response. These results suggest the novel hypothesis that the cerebellar overactivity observed in neuroimaging studies of patients with dystonia may be an indirect reflection of abnormal glutamate signaling. In addition, these results imply that reducing AMPA receptor activation by blocking AMPA receptors and promoting AMPA receptor desensitization or negative allosteric modulators may prove to be beneficial for treating dystonia.