Glutamate-system defects behind psychiatric manifestations in a familial hemiplegic migraine type 2 disease-mutation mouse model.
Glutamate-system defects behind psychiatric manifestations in a familial hemiplegic migraine type 2 disease-mutation mouse model.
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DOI：
10.1038/srep22047
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发表时间：
2016-02-25
影响因子：
4.6
通讯作者：
Lykke-Hartmann K
中科院分区：
文献类型：
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作者：
Bøttger P;Glerup S;Gesslein B;Illarionova NB;Isaksen TJ;Heuck A;Clausen BH;Füchtbauer EM;Gramsbergen JB;Gunnarson E;Aperia A;Lauritzen M;Lambertsen KL;Nissen P;Lykke-Hartmann K
偏头痛是一种复杂的大脑疾病，了解这种流行疾病的复杂性可以改善数百万人的生活质量。家族性偏瘫偏头痛2型（FHM 2）是偏头痛的一种亚型，具有先兆和合并症，如癫痫/癫痫发作，认知障碍和精神病表现，如强迫症（OCD）。FHM 2疾病突变定位于ATP 1A 2基因，该基因编码位于星形胶质细胞的钠-钾泵（α 2 Na +/K+-ATP酶）的α2亚型。我们发现，FHM 2相关G301 R突变（α2+/G301 R）杂合子敲入小鼠表型复制了几种FHM 2相关疾病特征，例如，通过模仿情绪抑郁症和强迫症体外研究表明，α 2 +/G301 R E17胚胎小鼠海马星形胶质细胞-神经元混合培养物中谷氨酸摄取受损，此外，诱导皮质扩散性抑制（CSD）导致α2+/G301 R雄性小鼠恢复减少。此外，NMDA型谷氨酸受体拮抗剂或仅孕激素治疗可逆转特异性α2+/G301 R行为表型。我们的研究结果表明，体内相关的FHM 2疾病基因敲入小鼠模型的研究提供了女性性激素周期和谷氨酸系统之间的联系，并与FHM 2的共病精神病学表现的联系。
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 α2G301R/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.