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

Sarah E. Smith, Xiaoying Chen, Lindsey M. Brier, Jonathan R. Bumstead, Nicholas R. Rensing, Alison E. Ringel, Haewon Shin, Anna Oldenborg, Jan R. Crowley, Annie R. Bice, Krikor Dikranian, Joseph E. Ippolito, Marcia C. Haigis, Thomas Papouin, Guoyan Zhao, Michael Wong, Joseph P. Culver & Azad Bonni. Nature Communications, Volume 11, Issue 1, December 2020, Article number 6164 Read More

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. © 2020, The Author(s).

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Posted on December 14, 2020
Posted in: Axon Injury & Repair, Clocks & Sleep, Neurogenetics & Transcriptomics, Publications Authors: , , , ,