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

被引：71

作者：

Bottger, Pernille ^{[1
,2
,3
]}

Glerup, Simon ^{[1
,4
]}

Gesslein, Bodil ^{[5
,6
]}

Illarionova, Nina B. ^{[7
]}

Isaksen, Toke J. ^{[1
,2
]}

Heuck, Anders ^{[1
,2
]}

Clausen, Bettina H. ^{[3
]}

Fuchtbauer, Ernst-Martin ^{[8
]}

Gramsbergen, Jan B. ^{[3
]}

Gunnarson, Eli ^{[7
]}

Aperia, Anita ^{[7
]}

Lauritzen, Martin ^{[5
,6
,9
]}

Lambertsen, Kate L. ^{[3
]}

Nissen, Poul ^{[8
,10
,11
]}

Lykke-Hartmann, Karin ^{[1
,2
,12
]}

机构：

[1] Aarhus Univ, Dept Biomed, DK-8000 Aarhus, Denmark

[2] Aarhus Univ, Dept Mol Biol & Genet, Danish Natl Res Fdn, Ctr Membrane Pumps Cells & Dis PUMPKIN, DK-8000 Aarhus C, Denmark

[3] Univ Southern Denmark, Inst Mol Med, Dept Neurobiol Res, DK-5000 Odense, Denmark

[4] Aarhus Univ, Dept Biomed, Lundbeck Fdn Res Ctr MIND, DK-8000 Aarhus C, Denmark

[5] Univ Copenhagen, Dept Neurosci & Pharmacol, DK-2200 Copenhagen N, Denmark

[6] Ctr Hlth Aging, DK-2200 Copenhagen N, Denmark

[7] Karolinska Inst, Dept Womens & Childrens Hlth, SE-17176 Stockholm, Sweden

[8] Aarhus Univ, Dept Mol Biol & Genet, DK-8000 Aarhus, Denmark

[9] Glostrup Cty Hosp, Dept Clin Neurophysiol, DK-2600 Glostrup, Denmark

[10] Aarhus Univ, Dept Mol Biol & Genet, Nord EMBL Partnership Mol Med, Danish Res Inst Translat Neurosci DANDRITE, DK-8000 Aarhus C, Denmark

[11] Dept Biomed, DK-8000 Aarhus C, Denmark

[12] Aarhus Univ, Aarhus Inst Adv Studies, Hoegh Guldbergs Gade 6B, DK-8000 Aarhus C, Denmark

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

基金：

英国医学研究理事会; 新加坡国家研究基金会; 瑞典研究理事会;

关键词：

CORTICAL SPREADING DEPRESSION; OBSESSIVE-COMPULSIVE DISORDER; NA; K-ATPASE ALPHA-2 ISOFORM; CEREBRAL-BLOOD-FLOW; NEURONAL-ACTIVITY; NMDA RECEPTOR; ANIMAL-MODELS; LINKAGE SCAN; MICE; RAT;

D O I：

10.1038/srep22047

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 alpha(2)-isoform of the sodium-potassium pump (alpha Na-2(+)/K+-ATPase). We show that knock-in mice heterozygous for the FHM2-associated G301R-mutation (alpha(+/G301R)(2)) 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 alpha(G301R/G301R)(2) E17 embryonic mice, and moreover, induction of cortical spreading depression (CSD) resulted in reduced recovery in alpha(+/G301R)(2) male mice. Moreover, NMDA-type glutamate receptor antagonists or progestin-only treatment reverted specific alpha(+/G301R)(2) 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.

引用

页数：21

共 94 条

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