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

TY - JOUR

T1 - Glutamate-system defects behind psychiatric manifestations in a familial hemiplegic migraine type 2 disease-mutation mouse model

AU - Bøttger, Pernille

AU - Pedersen, Simon Glerup

AU - Gesslein, Bodil

AU - Illarionova, Nina

AU - Isaksen, Toke Jost

AU - Heuck, Anders

AU - Clausen, Bettina Hjelm

AU - Füchtbauer, Ernst-Martin

AU - Gramsbergen, Jan Bert

AU - Gunnarson, Eli

AU - Aperia, Anita

AU - Lauritzen, Martin

AU - Lambertsen, Kate Lykke

AU - Nissen, Poul

AU - Lykke-Hartmann, Karin

PY - 2016/2/25

Y1 - 2016/2/25

N2 - 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.

AB - 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.

U2 - 10.1038/srep22047

DO - 10.1038/srep22047

M3 - Journal article

C2 - 26911348

SN - 2045-2322

VL - 6

JO - Scientific Reports

JF - Scientific Reports

IS - 22047

M1 - 22047

ER -