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Sci Rep. 2016 Feb 25;6:22047. doi: 10.1038/srep22047.

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

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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.
The Lundbeck Foundation Research Centre MIND, Aarhus University, Department of Biomedicine, DK-8000 Aarhus C, Denmark.
University of Copenhagen, Department of Neuroscience and Pharmacology and Center for Healthy Aging, DK-2200 Copenhagen N, Denmark.
Karolinska Institutet, Department of Women's and Children's Health, SE-171 76 Stockholm, Sweden.
Aarhus University, Department of Molecular Biology and Genetics, DK-8000 Aarhus, Denmark.
Glostrup Hospital, Department of Clinical Neurophysiology, DK-2600 Glostrup, 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.
Aarhus Institute of Advanced Studies, Aarhus University, Høegh-Guldbergs Gade 6B DK-8000 Aarhus C, Denmark.


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.

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