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

• Published in: Scientific reports Vol. 6; no. 1; p. 22047
• Main Authors: Bøttger, Pernille, Glerup, Simon, Gesslein, Bodil, Illarionova, Nina B., Isaksen, Toke J., Heuck, Anders, Clausen, Bettina H., Füchtbauer, Ernst-Martin, Gramsbergen, Jan B., Gunnarson, Eli, Aperia, Anita, Lauritzen, Martin, Lambertsen, Kate L., Nissen, Poul, Lykke-Hartmann, Karin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.02.2016; Nature Publishing Group
• Subjects: 631/378/1689; 64; 64/60; 692/617/375/1654; 82/80; 9/30; Acoustic Stimulation; Animals; ATP1A2 gene; Behavior, Animal; Biological Transport; Cerebrovascular Circulation; Cognitive ability; Computational Biology - methods; Cortex; Cortical spreading depression; Cortical Spreading Depression - genetics; Disease Models, Animal; Embryos; Epilepsy; Female; Glutamic acid; Glutamic Acid - metabolism; Glutamic acid receptors (ionotropic); Gonadal Steroid Hormones - metabolism; Headache; Hippocampus; Humanities and Social Sciences; Male; Medicin och hälsovetenskap; Mice; Mice, Transgenic; Migraine; Migraine with Aura - diagnosis; Migraine with Aura - drug therapy; Migraine with Aura - genetics; Migraine with Aura - metabolism; Mimicry; Mood; Motor Activity; multidisciplinary; Mutation; N-Methyl-D-aspartic acid receptors; Na+/K+-exchanging ATPase; Obsessive compulsive disorder; Phenotype; Progestin; Quality of life; Reaction Time; Rodents; Science; Science (multidisciplinary); Seizures; Sodium; Sodium-Potassium-Exchanging ATPase - genetics; Stress, Physiological
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep22047

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 α 2 -isoform of the sodium-potassium pump (α 2 Na + /K + -ATPase). 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. 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. Moreover, NMDA-type glutamate receptor antagonists or progestin-only treatment reverted specific α 2 +/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.