Comparative characterization of AHC associated mutations in ATP1A3 reveals diverse neurological alterations in mice.

Pathogenic variants the neuronal Na+/K+ ATPase transmembrane ion transporter (ATP1A3) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most common pathogenic variants in AHC are the p.D801N (~40%) and p.E815K (~25%) variant, which lead to spontaneous death with early mortality in mice. Nevertheless, the characterization and knowledge on the development of clinically relevant neurological phenotypes without the induction of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting to mitigate the fragility of AHC mice and then, combined behavioral, electrophysiological, biochemical, and molecular testing to comparatively analyze mice that carry the most common patient observed p.D801N and p.E815K variant in the Atp1a3 gene. Collectively, our data reveal the presence but also the differential impact of the p.D801N and p.E815K variant on disease relevant alterations such as spontaneous and stress-induced paroxysmal episodes, motor function, behavioral and neurophysiological activity, and neuroinflammation. Our alternate AHC mouse models and their phenotypic deficits open novel avenues for the investigation of disease biology and therapeutic testing for ATP1A3 research.