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

Abstract

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.

Mechanisms of increased hippocampal excitability in the Mashl+/− mouse model of Na+/K+‐ATPase dysfunction

“…This sustained increase of GABA could potentially lead to internalization or desensitization of postsynaptic GABA A receptors. Consistent with our findings of abnormal firing in GABAergic neurons is that 2 other models of Atp1a3 mutations manifest abnormalities in cerebellar GABAergic neuronal firing . Whereas the types of observed abnormalities differ among the 3 models, this is likely to be due to differences in the type of cells studied in the ages investigated, and to the likely different effects of different mutations.…”

“…Indeed, the Na + /K + ‐ATPase current density (or its activity) is known to be 3‐to 7‐fold larger in fast‐spiking interneurons than in cortical pyramidal neurons . In addition, increases in K + concentration due to seizure activity could further impair mutated pump function resulting depolarization block of fast‐spiking interneurons . An additional potential could involve upregulation of calcium‐dependent potassium currents in these interneurons.…”

“…Consistent with our findings of abnormal firing in GABAergic neurons is that 2 other models of Atp1a3 mutations manifest abnormalities in cerebellar GABAergic neuronal firing. 16,30 Whereas the types of observed abnormalities differ among the 3 models, this is likely to be due to differences in the type of cells studied in the ages investigated, and to the likely different effects of different mutations. For example, the D801N mutation shows a dominant negative effect when expressed in Xenopus laevis oocytes, 32 whereas knocking out the gene is not expected to do so.…”

PRRT2-dependent dyskinesia: cerebellar, paroxysmal and persistent

“…By providing the next example of a paroxysmal movement disorder that primarily originates in the cerebellum, rather than in the basal ganglia-thalamic circuit, the current paper is further opening up the avenue of research that aims to elucidate how deficits in the activity of Purkinje cells and/or that of their inputs can lead to movement disorders like PKD and RODP. So far, various in vivo datasets indicate that bursty and irregular Purkinje cell activity can result in abnormal movements, including not only dystonic [7,8] but also ataxic [9] movements. The current in vitro data obtained from PRRT2 mutants support this hypothesis in that the firing frequency of their Purkinje cell activity following optogenetic stimulation of their parallel fiber input was transiently and biphasically increased and decreased as compared to wild-type cells.…”

“…Does it merely depend on the initial event that evoked the abnormal firing pattern of Purkinje cells, which could include for example a period with seizures, stress or hyperthermia [2], or does it also depend on internal amplification mechanisms, such as those that are mediated by the projections from the cerebellar nuclei neurons to the granule cells in the cerebellar cortex [10] (Figure 1)? Given the similarities in duration of the behavioral and cerebellar neuronal correlates of the paroxysmal attacks in RODP mice [7,8] and that of the dysfunctional motor episodes in the murine models described in the paper by Tan and colleagues [2], it appears plausible that in both RODP and PKD prolonged interactive, yet erratic, firing patterns of Purkinje cells and their downstream targets in the nuclei underlie the pathological motor behavior.…”