文献类型：期刊文献

英文题名：Programming for increased expression of hippocampal GAD67 mediated the hypersensitivity of the hypothalamic-pituitary-adrenal axis in male offspring rats with prenatal ethanol exposure

作者：Lu, Juan[1,4];Jiao, Zhexiao[1];Yu, Ying[2,3];Zhang, Chong[1];He, Xia[1];Li, Qiang[4];Xu, Dan[1,2];Wang, Hui[1,2]

第一作者：Lu, Juan

通信作者：Xu, D[1];Wang, H[1];Xu, D[2];Wang, H[2]

机构：[1]Wuhan Univ, Basic Med Sch, Dept Pharmacol, Wuhan, Hubei, Peoples R China;[2]Hubei Prov Key Lab Dev Originated Dis, Wuhan, Hubei, Peoples R China;[3]Wuhan Univ, Renmin Hosp, Dept Neurol, Wuhan 430060, Hubei, Peoples R China;[4]Gansu Univ Chinese Med, Gansu Prov Hosp TCM, Lanzhou 730050, Gansu, Peoples R China

第一机构：Wuhan Univ, Basic Med Sch, Dept Pharmacol, Wuhan, Hubei, Peoples R China

通信机构：[1]corresponding author), Wuhan Univ, Basic Med Sch, Dept Pharmacol, Wuhan, Hubei, Peoples R China;[2]corresponding author), Hubei Prov Key Lab Dev Originated Dis, Wuhan, Hubei, Peoples R China.

年份：2018

卷号：9

期号：6

外文期刊名：CELL DEATH & DISEASE

收录：;Scopus(收录号：2-s2.0-85047973429);WOS:【SCI-EXPANDED(收录号:WOS:000433921800002)】；

基金：This work was supported by the National Natural Science Foundation of China (No. 81660544, 81430089, 81673524 and 81671472), the National Key Research and Development Programme of China (No. 2017YFC1001300), and Hubei Province Health and Family Planning Scientific Research Project (No. WJ2017C0003).

语种：英文

摘要：An imbalance of excitatory and inhibitory signals in the brain has been proposed to be one of the main pathological features of various diseases related to hypothalamic-pituitary-adrenal axis (HPAA) dysfunction. Excessive glutamate release induces neuronal excitotoxicity, while glutamic acid decarboxylase (GAD) 67 promotes the transformation of excessive glutamate to.-aminobutyric acid (GABA). Our previous studies demonstrated that prenatal ethanol exposure (PEE) causes foetal over-exposure to maternal corticosterone and hypersensitivity of the HPAA after birth, but its intrauterine programming mechanism is unknown. In this study, PEE was shown to lead to an enhanced potential excitatory ability of the hypothalamus and hypersensitivity of the HPAA, as well as mild abnormal hippocampal morphology, demethylation of the -1019 to -691-bp region in the hippocampal GAD67 promoter and upregulation of GAD67 expression accompanied by a reduction in glutamatergic neurons and increase in GABAergic neurons in PEE male offspring. Similar changes were also found in PEE male foetal rats. Furthermore, corticosterone increased the expression of the glucocorticoid receptor (GR) and GAD67 in foetal hippocampal H19-7 cells in a concentration-dependent manner, accompanied by demethylation of the GAD67 promoter, a decrease in glutamatergic neurons and increase in GABAergic neurons. The GR inhibitor, mifepristone, reversed the effects of corticosterone on H19-7 cells. These results suggested that PEE-induced excessive corticosterone can lead to upregulation of GAD67 through epigenetic modification mediated by the GR in the male foetal hippocampus, thereby weakening the negative regulation of the HPAA by the hippocampus and increasing the potential excitatory ability of the hypothalamus. These changes persisted until after birth, resulting in hypersensitivity of the HPAA. However, gender differences were observed in the hippocampal development, morphology and GAD67 expression associated with PEE. Programming for the increased expression of hippocampal GAD67 is a potential mechanism responsible for the hypersensitivity of the HPAA in PEE male rats.