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

Pernille Bøttger, Simon Glerup, Bodil Gesslein, Nina B. Illarionova, Toke J. Isaksen, Anders Heuck, Bettina Hjelm Clausen, Ernst-Martin Füchtbauer, Jan Bert Gramsbergen, Eli Gunnarson, Anita Aperia, Martin Lauritzen, Kate Lykke Lambertsen, Poul Nissen, Karin Lykke-Hartmann

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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 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.

Original languageEnglish
Article number22047
JournalScientific Reports
Volume6
Number of pages21
ISSN2045-2322
DOIs
Publication statusPublished - 25. Feb 2016

Keywords

  • Acoustic Stimulation
  • Animals
  • Behavior, Animal
  • Biological Transport
  • Cerebrovascular Circulation
  • Computational Biology/methods
  • Cortical Spreading Depression/genetics
  • Disease Models, Animal
  • Female
  • Glutamic Acid/metabolism
  • Gonadal Steroid Hormones/metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Migraine with Aura/diagnosis
  • Motor Activity
  • Mutation
  • Phenotype
  • Reaction Time
  • Sodium-Potassium-Exchanging ATPase/genetics
  • Stress, Physiological

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