Astrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway

Familial hemiplegic migraine is an episodic neurological disorder characterized by transient sensory and motor symptoms and signs. Mutations of the ion pump alpha 2-Na/K ATPase cause familial hemiplegic migraine, but the mechanisms by which alpha 2-Na/K ATPase mutations lead to the migraine phenotype remain incompletely understood. Here, we show that mice in which alpha 2-Na/K ATPase is conditionally deleted in astrocytes display episodic paralysis. Functional neuroimaging reveals that conditional alpha 2-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 alpha 2-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 alpha 2-Na/K ATPase knockout mice. Together, our findings define a metabolic mechanism regulated by astrocytic alpha 2-Na/K ATPase that triggers episodic motor paralysis in mice. Mutations of alpha 2-Na/K ATPase can cause familial hemiplegic migraine via unclear mechanisms. Here, the authors show that deletion of alpha 2-Na/K ATPase in astrocytes results in gene expression and metabolic changes leading to cortical spreading depression and episodic transient motor paralysis in mice.