ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in a dystonia model.

Akkuratov EE, Sorrell F, Picton L, Sousa VC, Paucar M, Jans D, Svensson LB, Lindskog M, Fritz N, Liebmann T, Sillar KT, Rosewich H, Svenningsson P, Brismar H, Miles GB, Aperia A

Brain - (-) - [2024-11-13; online 2024-11-13]

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.

Integrated Microscopy Technologies Stockholm [Service]

PubMed 39533828

DOI 10.1093/brain/awae373

Crossref 10.1093/brain/awae373

pii: 7896743