title: Glutamate-system defects behind psychiatric manifestations in a familial hemiplegic migraine type 2 disease-mutation mouse model.
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 α2(G301R/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.
authors.affiliation: Aarhus University, Department of Biomedicine, DK-8000 Aarhus, Denmark.|Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Aarhus University, Department of Molecular Biology and Genetics, DK-8000 Aarhus C, Denmark.|University of Southern Denmark, Institute of Molecular Medicine, Department of Neurobiology Research, DK-5000 Odense, Denmark.
authors.forename: Pernille
authors.initials: P
authors.lastname: Bøttger
authors.affiliation: Aarhus University, Department of Biomedicine, DK-8000 Aarhus, Denmark.|The Lundbeck Foundation Research Centre MIND, Aarhus University, Department of Biomedicine, DK-8000 Aarhus C, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Glerup
authors.affiliation: University of Copenhagen, Department of Neuroscience and Pharmacology and Center for Healthy Aging, DK-2200 Copenhagen N, Denmark.
authors.forename: Bodil
authors.initials: B
authors.lastname: Gesslein
authors.affiliation: Karolinska Institutet, Department of Women's and Children's Health, SE-171 76 Stockholm, Sweden.
authors.forename: Nina B
authors.initials: NB
authors.lastname: Illarionova
authors.affiliation: Aarhus University, Department of Biomedicine, DK-8000 Aarhus, Denmark.|Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Aarhus University, Department of Molecular Biology and Genetics, DK-8000 Aarhus C, Denmark.
authors.forename: Toke J
authors.initials: TJ
authors.lastname: Isaksen
authors.affiliation: Aarhus University, Department of Biomedicine, DK-8000 Aarhus, Denmark.|Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Aarhus University, Department of Molecular Biology and Genetics, DK-8000 Aarhus C, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Heuck
authors.affiliation: University of Southern Denmark, Institute of Molecular Medicine, Department of Neurobiology Research, DK-5000 Odense, Denmark.
authors.forename: Bettina H
authors.initials: BH
authors.lastname: Clausen
authors.affiliation: Aarhus University, Department of Molecular Biology and Genetics, DK-8000 Aarhus, Denmark.
authors.forename: Ernst-Martin
authors.initials: EM
authors.lastname: Füchtbauer
authors.affiliation: University of Southern Denmark, Institute of Molecular Medicine, Department of Neurobiology Research, DK-5000 Odense, Denmark.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Gramsbergen
authors.affiliation: Karolinska Institutet, Department of Women's and Children's Health, SE-171 76 Stockholm, Sweden.
authors.forename: Eli
authors.initials: E
authors.lastname: Gunnarson
authors.affiliation: Karolinska Institutet, Department of Women's and Children's Health, SE-171 76 Stockholm, Sweden.
authors.forename: Anita
authors.initials: A
authors.lastname: Aperia
authors.affiliation: University of Copenhagen, Department of Neuroscience and Pharmacology and Center for Healthy Aging, DK-2200 Copenhagen N, Denmark.|Glostrup Hospital, Department of Clinical Neurophysiology, DK-2600 Glostrup, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Lauritzen
authors.affiliation: University of Southern Denmark, Institute of Molecular Medicine, Department of Neurobiology Research, DK-5000 Odense, Denmark.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Lambertsen
authors.affiliation: Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Aarhus University, Department of Molecular Biology and Genetics, DK-8000 Aarhus C, Denmark.|Aarhus University, Department of Molecular Biology and Genetics, DK-8000 Aarhus, Denmark.|Danish Research Institute for Translational Neuroscience-DANDRITE, Nordic-EMBL Partnership of Molecular Medicine, Aarhus University, Department of Molecular Biology and Genetics and Department of Biomedicine, DK-8000 Aarhus C, Denmark.
authors.forename: Poul
authors.initials: P
authors.lastname: Nissen
authors.affiliation: Aarhus University, Department of Biomedicine, DK-8000 Aarhus, Denmark.|Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Aarhus University, Department of Molecular Biology and Genetics, DK-8000 Aarhus C, Denmark.|Aarhus Institute of Advanced Studies, Aarhus University, Høegh-Guldbergs Gade 6B DK-8000 Aarhus C, Denmark.
authors.forename: Karin
authors.initials: K
authors.lastname: Lykke-Hartmann
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D001522:Behavior, Animal; D001692:Biological Transport; D002560:Cerebrovascular Circulation; D019295:Computational Biology / Q000379:methods; D013181:Cortical Spreading Depression / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020325:Migraine with Aura / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D009043:Motor Activity; D009154:Mutation; D010641:Phenotype; D011930:Reaction Time; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics; D013312:Stress, Physiological
chemical_list: D012739:Gonadal Steroid Hormones; D018698:Glutamic Acid; C401838:Atp1a2 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase