Na + /K + -ATPase α isoform deficiency results in distinct spreading depolarization phenotypes.

Compromised Na+/K+-ATPase function is associated with the occurrence of spreading depolarization (SD). Mutations in ATP1A2, the gene encoding the alpha 2 isoform of the Na+/K+-ATPase, were identified in patients with familial hemiplegic migraine type 2 (FHM2), a Mendelian model disease for SD. This suggests a distinct role for the alpha 2 isoform in modulating SD susceptibility and raises questions about underlying mechanisms including the roles of other Na+/K+-ATPase alpha isoforms. Here, we investigated the effects of genetic ablation and pharmacological inhibition of alpha 1, alpha 2, and alpha 3 on SD using heterozygous knock-out mice. We found that only alpha 2 heterozygous mice displayed higher SD susceptibility when challenged with prolonged extracellular high potassium concentration ([K+](o)), a pronounced post SD oligemia and higher SD speed in-vivo. By contrast, under physiological [K+](o), alpha 2 heterozygous mice showed similar SD susceptibility compared to wild-type littermates. Deficiency of alpha 3 resulted in increased resistance against electrically induced SD in-vivo, whereas alpha 1 deficiency did not affect SD. The results support important roles of the alpha 2 isoform in SD. Moreover, they suggest that specific experimental conditions can be necessary to reveal an inherent SD phenotype by driving a (meta-) stable system into decompensation, reminiscent of the episodic nature of SDs in various diseases.