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 α3isoform 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 (α3 +/d801y),suffer abrupt hypothermia-induced dystonia identified by electromyographic recordings. single-neuron in vivo recordings in awake α3 +/d801ymice 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 α3isoform-related dystonia and add to the functional understanding of the scarce and severe mutations in the α3isoform na+/k+-atpase. © 2017 isaksen et al.