ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in as dystonia model

Mutations in the gene encoding the alpha3 Na⁺/K⁺-ATPase isoform (ATP1A3) lead to movement disorders that manifest with dystonia, a common neurological symptom with many different origins, but for which the underlying molecular mechanisms remain poorly understood.

We have generated an ATP1A3 mutant mouse that displays motor impairments and a hyperexcitable motor phenotype compatible with dystonia. We show that neurons harboring this mutation are compromised in their ability to extrude raised levels of intracellular sodium, highlighting a profound deficit in neuronal sodium homeostasis. We show that the spinal motor network in ATP1A3 mutant mice has a reduced responsiveness to activity-dependent rises in intracellular sodium and that this is accompanied by loss of the Na⁺/K⁺-ATPase-mediated afterhyperpolarization in motor neurons.

Taken together, our data support that the alpha3 Na⁺/K⁺-ATPase is important for cellular and spinal motor network homeostasis. These insights suggest that it may be useful to consider ways to compensate for this loss of a critical afterhyperpolarization-dependent control of neuronal excitability when developing future therapies for dystonia.