The sodium 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. In the majority of FHM2-families, the disease is caused by haploinsufficiency due to loss-of-function mutations in the ATP1A2-gene, which encodes the α 2-isoform of the Na +/K +-ATPase (a sodium pump) 2, 6. FHM2 is a rare form of migraine with aura that involves motor aura (weakness) and frequently accompanied by co-morbid epilepsy/seizures 2, 3, and in a subset of FHM2-families cognitive impairments and/or different psychiatric manifestations such as mood depression, anxiety and obsessive compulsive disorder (OCD) have been reported 2, 4 as well as co-occurrence of obesity and other migraine forms 5, 2. 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.įamilial Hemiplegic Migraine type 2 (FHM2) is a chronic and hereditary disorder with severe episodic attacks of migraine with aura (MA) fulfilling the classic migraine criteria 1. Moreover, NMDA-type glutamate receptor antagonists or progestin-only treatment reverted specific α 2 +/G301R behavioral phenotypes. In vitro studies showed impaired glutamate uptake in hippocampal mixed astrocyte-neuron cultures from α 2 G301R/G301R E17 embryonic mice, and moreover, induction of cortical spreading depression (CSD) resulted in reduced recovery in α 2 +/G301R male mice. We show that knock-in mice heterozygous for the FHM2-associated G301R-mutation (α 2 +/G301R) phenocopy several FHM2-relevant disease traits e.g., by mimicking mood depression and OCD. FHM2 disease-mutations locate to the ATP1A2 gene encoding the astrocyte-located α 2-isoform of the sodium-potassium pump (α 2Na +/K +-ATPase). 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). Migraine is a complex brain disorder, and understanding the complexity of this prevalent disease could improve quality of life for millions of people.
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