Glutamate-system defects behind psychiatric manifestations in a familial hemiplegic migraine type 2 disease-mutation mouse model
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Glutamate-system defects behind psychiatric manifestations in a familial hemiplegic migraine type 2 disease-mutation mouse model. / 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.
I: Scientific Reports, Bind 6, 22047, 25.02.2016.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Glutamate-system defects behind psychiatric manifestations in a familial hemiplegic migraine type 2 disease-mutation mouse model
AU - Bøttger, Pernille
AU - Glerup, Simon
AU - Gesslein, Bodil
AU - Illarionova, Nina B
AU - Isaksen, Toke J
AU - Heuck, Anders
AU - Clausen, Bettina H
AU - Füchtbauer, Ernst-Martin
AU - Gramsbergen, Jan B
AU - Gunnarson, Eli
AU - Aperia, Anita
AU - Lauritzen, Martin
AU - Lambertsen, Kate L
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 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.
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 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.
U2 - 10.1038/srep22047
DO - 10.1038/srep22047
M3 - Journal article
C2 - 26911348
VL - 6
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 22047
ER -
ID: 167472653