| First Author | Reiffurth C | Year | 2020 |
| Journal | J Cereb Blood Flow Metab | Volume | 40 |
| Issue | 3 | Pages | 622-638 |
| PubMed ID | 30819023 | Mgi Jnum | J:296526 |
| Mgi Id | MGI:6467901 | Doi | 10.1177/0271678X19833757 |
| Citation | Reiffurth C, et al. (2020) Na(+)/K(+)-ATPase alpha isoform deficiency results in distinct spreading depolarization phenotypes. J Cereb Blood Flow Metab 40(3):622-638 |
| abstractText | Compromised Na(+)/K(+)-ATPase function is associated with the occurrence of spreading depolarization (SD). Mutations in ATP1A2, the gene encoding the alpha2 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 alpha2 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 alpha1, alpha2, and alpha3 on SD using heterozygous knock-out mice. We found that only alpha2 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, alpha2 heterozygous mice showed similar SD susceptibility compared to wild-type littermates. Deficiency of alpha3 resulted in increased resistance against electrically induced SD in-vivo, whereas alpha1 deficiency did not affect SD. The results support important roles of the alpha2 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. |
