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

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.

Migraine Aura, Transient Ischemic Attacks, Stroke, and Dying of the Brain Share the Same Key Pathophysiological Process in Neurons Driven by Gibbs–Donnan Forces, Namely Spreading Depolarization

“…Thus, the fact that some migraine auras have a vascular etiology does not mean that all migraine auras have a vascular etiology ( van den Maagdenberg et al, 2004 ; Leo et al, 2011 ; Brennan et al, 2013 ; Dreier and Reiffurth, 2015 ; Jansen et al, 2020 ). It has been particularly well established clinically and in animal experiments for familial hemiplegic migraine (FHM) types 1 and 3 as examples of primary neuronal disorders ( Vahedi et al, 2000 ; Ducros et al, 2001 ; van den Maagdenberg et al, 2004 ; Dichgans et al, 2005 ; Jansen et al, 2020 ) and for FHM type 2 as an example of a primary astrocytic disorder ( De Fusco et al, 2003 ; Jurkat-Rott et al, 2004 ; Dreier et al, 2005 ; Leo et al, 2011 ; Reiffurth et al, 2020 ; Smith et al, 2020 ; Parker et al, 2021 ) that not only primary vascular but also primary neuronal and primary astrocytic dysfunctions can lead to spreading depolarization. Indeed, it was already known before the discovery of FHM mutations that primary astrocytic dysfunction is a potent trigger of spreading depolarization ( Largo et al, 1996b ).…”

A hyperthermic seizure unleashes a surge of spreading depolarizations inScn1adeficient mice

“…Such prodromal behavior activation likely reflects the local brain excitation associated with SD generation. A study in an α2-Na/K ATPase conditional KO mouse also described a paralyzing effect of putative cortical SD events 44 , however the paralysis status described in that study more closely resembles postictal coma than immobility. Postictal immobility has been linked to the risk of severe respiratory dysfunction and sudden unexpected death in epilepsy (SUDEP) 20 .…”

Neuron‐glia (mis)interactions in brain energy metabolism during aging

“…Decreases in various mRNA isoforms encoding the pump were described in aged rat brains (de Lores Arnaiz & Ordieres, 2014). This is particularly interesting because astrocyte‐specific KO of the α2‐Na + /K + ‐ATPase isoform generates motor paralysis in mice (Smith et al., 2020).…”