ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in a 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 harbouring 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.
Authors
- Hendrik Rosewich (ORCID: https://orcid.org/0000-0003-4692-5511)
- Nicolas Fritz (ORCID: https://orcid.org/0000-0002-9722-7425)
- Maria Lindskog (ORCID: https://orcid.org/0000-0002-4178-2825)
- Keith T. Sillar (ORCID: https://orcid.org/0000-0003-0171-3814)
- Evgeny E. Akkuratov (ORCID: https://orcid.org/0000-0002-2552-9512)
- Daniel C. Jans (ORCID: https://orcid.org/0000-0002-6356-9742)
- Anita Aperia (ORCID: https://orcid.org/0000-0002-9101-2052)
- Per Svenningsson (ORCID: https://orcid.org/0000-0001-6727-3802)
- Martin Paucar (ORCID: https://orcid.org/0000-0003-3735-1480)
- Gareth Brian Miles (ORCID: https://orcid.org/0000-0002-8624-4625)
- Thomas Liebmann
- Hjalmar Brismar (ORCID: https://orcid.org/0000-0003-0578-4003)
- Vasco C. Sousa (ORCID: https://orcid.org/0000-0002-0086-6168)
- Laurence D. Picton (ORCID: https://orcid.org/0000-0001-9311-408X)
- Lill-Britt Svensson
- Francesca L. Sorrell
Institutions
- Uppsala University (SE)
- University of St Andrews (GB)
- Science for Life Laboratory (SE)
- Karolinska Institutet (SE)
- Universitätsmedizin Göttingen (DE)
- University Children's Hospital Tübingen (DE)
- University of Göttingen (DE)
- University of Tübingen (DE)
- KTH Royal Institute of Technology (SE)
Publication Details
- Journal
- Brain
- Published
- 2024-11-13
- DOI
- https://doi.org/10.1093/brain/awae373
- Citations
- 4
- Primary Topic
- Ion channel regulation and function
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- Wellcome Trust
- Svenska Sällskapet för Medicinsk Forskning
- Vetenskapsrådet
- Biotechnology and Biological Sciences Research Council