Astrocyte Deletion of alpha2-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 alpha2-Na/K ATPase represent a key genetic cause of familial hemiplegic migraine, but the mechanisms by which alpha2-Na/K ATPase mutations lead to the migraine phenotype remain incompletely understood. Here, we unexpectedly find that mice in which alpha2-Na/K ATPase is conditionally deleted in astrocytes display episodic transient motor paralysis. Functional neuroimaging reveals that conditional knockout of alpha2-Na/K ATPase triggers spontaneous cortical spreading depression events that are associated with low voltage activity events upon EEG monitoring, which in turn correlate with transient motor impairment in these mice. Transcriptomic and metabolomic analyses show that loss of alpha2-Na/K ATPase alters metabolic gene expression in astrocytes in vivo with consequent elevation of serine and glycine in the brain. Strikingly, feeding alpha2-Na/K ATPase knockout mice a serine- and glycine-free diet reverses the phenotype of transient motor impairment. Together, our findings define a novel metabolic mechanism regulated by astrocytic alpha2-Na/K ATPase that triggers episodic transient motor paralysis in mice, laying the foundation for potential new treatment strategies for patients with familial hemiplegic migraine. Overall design: RNA-Seq and TRAP-Seq from Cortex