Glutamate-system defects behind psychiatric manifestations in a familial hemiplegic migraine type 2 disease-mutation mouse model

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 alpha(2)-isoform of the sodium-potassium pump (alpha Na-2(+)/K+-ATPase). We show that knock-in mice heterozygous for the FHM2-associated G301R-mutation (alpha(+/G301R)(2)) 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 alpha(G301R/G301R)(2) E17 embryonic mice, and moreover, induction of cortical spreading depression (CSD) resulted in reduced recovery in alpha(+/G301R)(2) male mice. Moreover, NMDA-type glutamate receptor antagonists or progestin-only treatment reverted specific alpha(+/G301R)(2) 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.