Abnormal cerebellar signaling induces dystonia in mice

by Pizoli, Carolyn E.

Dystonia is a relatively common neurological syndrome characterized by twisting movements or sustained abnormal postures. The pathophysiology of dystonia remains poorly understood; however, recent evidence suggests that abnormal cerebellar signaling contributes to the expression of dystonia. To study the role of the cerebellum in dystonia, we first analyzed neurotransmission in the cerebellum of the genetically dystonic mouse, tottering. A deficiency in excitatory but not inhibitory neurotransmission in tottering mice was seen after superfusion of cerebellar synaptosomes with 60mM KCl. Further analysis of the role of cerebellar Purkinje cells in the generation of tottering dystonia was completed through breeding a transgene responsible for post-developmental Purkinje cell death onto the tottering mouse. Prior to Purkinje cell degeneration, transgenic tottering mice exhibited classical tottering dystonic events; however, the same animals failed to exhibit dystonia after Purkinje cell loss had occurred in adulthood. The loss of the dystonic phenotype in double mutant mice indicates that Purkinje cells and the cerebellar cortex participate in the pathogenesis of dystonia in the tottering mouse. These data support the theory that an abnormal signal from the cerebellar cortex of tottering mice is responsible for the dystonic phenotype. To test this theory and examine the role of the cerebellum in dystonia, we developed a novel mouse model of dystonia. Microinjection of low-doses of the glutamate analogue kainic acid into the cerebellum of wild type mice elicited reliable and reproducible dystonia. Transgenic mice lacking Purkinje cells showed dramatically decreased dystonia after kainic acid injections, supporting the theory that aberrant cerebellar excitation is sufficient to produce dystonia. Together these data suggest that the cerebellum plays a role in the pathophysiology underlying dystonia. iv