Inactivation of the maternal fragile X gene results in sensitization of GABAB receptor function in the offspring.
Inactivation of the maternal fragile X gene results in sensitization of GABAB receptor function in the offspring.
复制标题
DOI：
10.1124/jpet.108.143990
复制
发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Toth M
中科院分区：
文献类型：
--
作者：
Zupan B;Toth M
脆性X染色体综合征是一种X染色体连锁疾病，由FMR-1基因失活引起，症状范围从认知功能受损到癫痫发作、焦虑、感觉异常和多动。虽然脆性X综合征被认为是一种典型的孟德尔疾病，但我们最近报道，环境，特别是fmr-1+/−或fmr-1−/−（H或KO）母体环境，本身会导致部分脆性X样表型，并可能导致fmr-1−/0（KO）雄性后代的整体表型。事实上，与H和KO母亲所生的KO雄性后代（H>KO和KO>KO）相似，H雌性所生的基因fmr-1+/0（WT）雄性（H母亲> WT后代）表现出运动过度活跃。这些小鼠还表现出D2自身受体功能降低，表明黑质纹状体和中脑边缘系统中多巴胺（DA）释放的反馈抑制可能减弱。GABA能系统还调节DA释放，部分通过位于中脑多巴胺能神经元上的突触前GABAB受体（Rs）。在这里，我们表明，与WT>WT小鼠相比，GABABR激动剂巴氯芬的运动抑制作用在突变型母亲的所有后代（H>WT，H>KO和KO>KO）中增强，而不管它们自己的基因型如何。然而，增加敏感性巴氯芬是选择性的，并限于运动反应，因为肌肉松弛和镇静作用的药物不改变母体环境。这些数据表明，GABABR敏化，传统上诱导的fmr-1缺陷的母体环境，也可以引起。
Fragile X syndrome is an X linked disorder caused by the inactivation of the FMR-1 gene with symptoms ranging from impaired cognitive functions to seizures, anxiety, sensory abnormalities and hyperactivity. Although Fragile X syndrome is considered a typical Mendelian disorder, we have recently reported that the environment, specifically the fmr-1+/− or fmr-1−/− (H or KO) maternal environment, elicits on its own a partial fragile X-like phenotype and can contribute to the overall phenotype of fmr-1−/0 (KO) male offspring. Indeed, genetically fmr-1+/0(WT) males born to H females (Hmaternal>WToffspring), similarly to KO male offspring born to H and KO mothers (H>KO and KO>KO), exhibit locomotor hyperactivity. These mice also showed reduced D2 autoreceptor function, indicating a possible diminished feedback inhibition of dopamine (DA) release in the nigrostriatal and mesolimbic systems. The GABAergic system also regulates DA release, in part via presynaptic GABAB receptors (Rs) located on midbrain dopaminergic neurons. Here we show that the locomotor inhibitory effect of the GABABR agonist baclofen is enhanced in all progeny of mutant mothers (H>WT, H>KO and KO>KO) as compared to WT>WT mice, irrespective of their own genotype. However, increased sensitivity to baclofen was selective and limited to the locomotor response because the muscle relaxant and sedative effects of the drug were not altered by the maternal environment. These data show that GABABR sensitization, traditionally induced pharmacologically, can also be elicited by the fmr-1 deficient maternal environment.
登录
查看更多内容
影响因子：
25
作者：
Cruz, HG;Ivanova, T;Lüscher, C
通讯作者：
Lüscher, C
个案研究--2 个月大婴儿因母亲残留注意力缺陷障碍而无法成长
DOI：
10.1097/00004583-199501000-00014
发表时间：
1995-01-01
影响因子：
13.3
作者：
DALY, JM;FRITSCH, SL
通讯作者：
FRITSCH, SL
DOI：
10.1002/ajmg.1320300138
发表时间：
1988-05-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
HAGERMAN, RJ;MURPHY, MA;WITTENBERGER, MD
通讯作者：
WITTENBERGER, MD
影响因子：
3.5
作者：
Peier, AM;McIlwain, KL;Nelson, DL
通讯作者：
Nelson, DL
影响因子：
5
作者：
Colombo, G;Melis, S;Gessa, GL
通讯作者：
Gessa, GL