title: Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2.
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 Atp1a2(R887/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.
authors: Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
authors: Loredana
authors: L
authors: Leo
authors: Lisa
authors: L
authors: Gherardini
authors: Virginia
authors: V
authors: Barone
authors: Maurizio
authors: M
authors: De Fusco
authors: Daniela
authors: D
authors: Pietrobon
authors: Tommaso
authors: T
authors: Pizzorusso
authors: Giorgio
authors: G
authors: Casari
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D013181:Cortical Spreading Depression / Q000235:genetics*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D055879:Gene Knock-In Techniques; D018698:Glutamic Acid / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020325:Migraine with Aura / Q000235:genetics / Q000473:pathology*; D016254:Mutagenesis, Insertional; D010641:Phenotype; D021381:Protein Transport; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission; D014162:Transfection
chemical_list: D018698:Glutamic Acid; C401838:Atp1a2 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase