Abstract
Migraine is a complex brain disorder, and understanding the complexity of this prevalent disease could improve quality of life for millions of people. Familial Hemiplegic Migraine type 2 (FHM2) is a subtype of migraine with aura and co-morbidities like epilepsy/seizures, cognitive impairments and psychiatric manifestations, such as obsessive-compulsive disorder (OCD). FHM2 disease-mutations locate to the ATP1A2 gene encoding the astrocyte-located α2-isoform of the sodium-potassium pump (α2Na+/K+-ATPase). We show that knock-in mice heterozygous for the FHM2-associated G301R-mutation (α2+/G301R) phenocopy several FHM2-relevant disease traits e.g., by mimicking mood depression and OCD. In vitro studies showed impaired glutamate uptake in hippocampal mixed astrocyte-neuron cultures from α2G301R/G301R E17 embryonic mice, and moreover, induction of cortical spreading depression (CSD) resulted in reduced recovery in α2+/G301R male mice. Moreover, NMDA-type glutamate receptor antagonists or progestin-only treatment reverted specific α2+/G301R behavioral phenotypes. Our findings demonstrate that studies of an in vivo relevant FHM2 disease knock-in mouse model provide a link between the female sex hormone cycle and the glutamate system and a link to co-morbid psychiatric manifestations of FHM2.
Highlights
Pump directs ion gradients (3Na+out/2K+in) which, in conjugation with other pump-independent functions, are implicated in various basic and specialized cellular functions
All behavioral experiments were done blind to genotype with age-matched littermates
The G→ A mutation in exon 8 encoding the Familial Hemiplegic Migraine type 2 (FHM2)-associated G301R-mutation was introduced by homologous recombination and resulted in α 2+/G301R knock-in (KI) mice (Supplementary Table 1 and Supplementary Fig. 1a)
Summary
Pump directs ion gradients (3Na+out/2K+in) which, in conjugation with other pump-independent functions, are implicated in various basic and specialized cellular functions. Two FHM1 knock-in mouse models[17,18] and an Atp1a2 mouse model harboring the W887R mutation[19] revealed increased susceptibility to CSD compared to WT mice supporting CSD as a trigger to migraine. In this regard, it is noteworthy that while most of the ATP1A2 mutations (and the W887R mutation) are associated with pure FHM2, the ATP1A2 G301R mutation represents a particular severe phenotype with an early onset. Our results link the female sex hormone cycle and the glutamate system and a link to co-morbid psychiatric manifestations of FHM2
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