Hypothermia-induced dystonia and abnormal cerebellar activity in a mouse model with a single disease-mutation in the sodium-potassium pump.
Toke Jost IsaksenKamran KhodakhahNatascia VedovatoThomas Hellesøe HolmAriel VitenzonDavid C GadsbyKamran KhodakhahKarin Lykke-HartmannPublished in: PLoS genetics (2017)
Mutations in the neuron-specific α3 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 (α3+/D801Y), suffer abrupt hypothermia-induced dystonia identified by electromyographic recordings. Single-neuron in vivo recordings in awake α3+/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 α3 isoform-related dystonia and add to the functional understanding of the scarce and severe mutations in the α3 isoform Na+/K+-ATPase.
Keyphrases
- deep brain stimulation
- early onset
- high frequency
- parkinson disease
- drug induced
- transcranial magnetic stimulation
- mouse model
- cardiac arrest
- high glucose
- end stage renal disease
- diabetic rats
- induced apoptosis
- ejection fraction
- high fat diet induced
- chronic kidney disease
- spinal cord
- prognostic factors
- spinal cord injury
- cell cycle arrest
- cell death
- insulin resistance
- single cell
- signaling pathway
- quantum dots
- prefrontal cortex
- pi k akt