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- Title
Astrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway.
- Authors
Smith, Sarah E.; Chen, Xiaoying; Brier, Lindsey M.; Bumstead, Jonathan R.; Rensing, Nicholas R.; Ringel, Alison E.; Shin, Haewon; Oldenborg, Anna; Crowley, Jan R.; Bice, Annie R.; Dikranian, Krikor; Ippolito, Joseph E.; Haigis, Marcia C.; Papouin, Thomas; Zhao, Guoyan; Wong, Michael; Culver, Joseph P.; Bonni, Azad
- Abstract
Familial hemiplegic migraine is an episodic neurological disorder characterized by transient sensory and motor symptoms and signs. Mutations of the ion pump α2-Na/K ATPase cause familial hemiplegic migraine, but the mechanisms by which α2-Na/K ATPase mutations lead to the migraine phenotype remain incompletely understood. Here, we show that mice in which α2-Na/K ATPase is conditionally deleted in astrocytes display episodic paralysis. Functional neuroimaging reveals that conditional α2-Na/K ATPase knockout triggers spontaneous cortical spreading depression events that are associated with EEG low voltage activity events, which correlate with transient motor impairment in these mice. Transcriptomic and metabolomic analyses show that α2-Na/K ATPase loss alters metabolic gene expression with consequent serine and glycine elevation in the brain. A serine- and glycine-free diet rescues the transient motor impairment in conditional α2-Na/K ATPase knockout mice. Together, our findings define a metabolic mechanism regulated by astrocytic α2-Na/K ATPase that triggers episodic motor paralysis in mice. Mutations of α2-Na/K ATPase can cause familial hemiplegic migraine via unclear mechanisms. Here, the authors show that deletion of α2-Na/K ATPase in astrocytes results in gene expression and metabolic changes leading to cortical spreading depression and episodic transient motor paralysis in mice.
- Subjects
SPREADING cortical depression; ADENOSINE triphosphatase; MIGRAINE aura; PARALYSIS; GLYCINE receptors; SYMPTOMS; KNOCKOUT mice; MICE
- Publication
Nature Communications, 2020, Vol 11, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-19915-2