Hypothermia-induced dystonia and abnormal cerebellar activity in a mouse model with a single disease-mutation in the sodium-potassium pump

Mutations in the neuron-specific α(3) isoform of the Na(+)/K(+)-ATPase are found in patients suffering from Rapid onset Dystonia Parkinsonism and Alternating Hemiplegia of Childhood, two closely related movement disorders. We show that mice harboring a heterozygous hot spot disease mutation, D801Y (α(3)(+/D801Y)), suffer abrupt hypothermia-induced dystonia identified by electromyographic recordings. Single-neuron in vivo recordings in awake α(3)(+/D801Y) mice revealed irregular firing of Purkinje cells and their synaptic targets, the deep cerebellar nuclei neurons, which was further exacerbated during dystonia and evolved into abnormal high-frequency burst-like firing. Biophysically, we show that the D-to-Y mutation abolished pump-mediated Na(+)/K(+) exchange, but allowed the pumps to bind Na(+) and become phosphorylated. These findings implicate aberrant cerebellar activity in α(3) isoform-related dystonia and add to the functional understanding of the scarce and severe mutations in the α(3) isoform Na(+)/K(+)-ATPase.