Increased Susceptibility to Cortical Spreading Depression in the Mouse Model of Familial Hemiplegic Migraine Type 2

Loredana Leo,Lisa Gherardini,Daniela Pietrobon,Virginia Barone,Tommaso Pizzorusso,Giorgio Casari,Maurizio De Fusco,Gregory A Cox

doi:10.1371/journal.pgen.1002129

Abstract

Familial hemiplegic migraine type 2 (FHM2) is an autosomal dominant form of migraine with aura that is caused by mutations of the α2-subunit of the Na,K-ATPase, an isoform almost exclusively expressed in astrocytes in the adult brain. We generated the first FHM2 knock-in mouse model carrying the human W887R mutation in the Atp1a2 orthologous gene. Homozygous Atp1a2R887/R887 mutants died just after birth, while heterozygous Atp1a2+/R887 mice showed no apparent clinical phenotype. The mutant α2 Na,K-ATPase protein was barely detectable in the brain of homozygous mutants and strongly reduced in the brain of heterozygous mutants, likely as a consequence of endoplasmic reticulum retention and subsequent proteasomal degradation, as we demonstrate in transfected cells. In vivo analysis of cortical spreading depression (CSD), the phenomenon underlying migraine aura, revealed a decreased induction threshold and an increased velocity of propagation in the heterozygous FHM2 mouse. Since several lines of evidence involve a specific role of the glial α2 Na,K pump in active reuptake of glutamate from the synaptic cleft, we hypothesize that CSD facilitation in the FHM2 mouse model is sustained by inefficient glutamate clearance by astrocytes and consequent increased cortical excitatory neurotransmission. The demonstration that FHM2 and FHM1 mutations share the ability to facilitate induction and propagation of CSD in mouse models further support the role of CSD as a key migraine trigger.

Highlights

Migraine is a clinically heterogeneous disorder affecting more than 10% of the general population
We previously reported that mutations of the a2 subunit of the Na,K-ATPase cause familial hemiplegic migraine type 2 (FHM2), a dominant form of migraine with aura
Given the evidence for specific functional coupling between the glial a2 Na,K pump and glutamate transporters, we hypothesize that cortical spreading depression (CSD) facilitation in the Familial hemiplegic migraine type 2 (FHM2) mouse model is sustained by inefficient glutamate clearance by astrocytes and consequent increased cortical excitatory neurotransmission

Summary

Introduction

Migraine is a clinically heterogeneous disorder affecting more than 10% of the general population. It generally occurs with unilateral and pulsating severe headache often accompanied by nausea, photophobia and phonophobia. The migraine attack is triggered by a brain dysfunction that leads to activation and sensitization of the trigeminovascular system, trigeminal nociceptive afferents innervating the meninges and lastly to headache [2,3,4]. Neuroimaging examination suggests that migraine aura is associated to cortical spreading depression (CSD), a short-lasting, intense wave of neuronal and glial cell depolarization. CSD spreads slowly over the cortex at a rate of approximately 2–5 mm/ min and is followed by long lasting depression of neuronal activity [5,6,7,8]. Several migraine prophylactic agents cause an increase of CSD initiation threshold [13]

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