No abstract

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 γ-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.

The intrauterine programming of hypothalamic-pituitary-adrenal (HPA) axis hypersensitivity is associated with chronic adult diseases. Our previous studies demonstrated the HPA-axis hypersensitivity in offspring rats induced by prenatal nicotine exposure. The goal of the present study is to further investigate the intrauterine programming mechanism. Pregnant Wistar rats were subcutaneously administered with 2.0 mg/kg day of nicotine from gestational day (GD) 9-20. A group of the pregnant rats was euthanized at GD20, and the fetal rats were extracted. The remaining rats were left to come to term, and the adult offspring were exposed to chronic stress. For adult offspring rats, prenatal nicotine exposure induced HPA-axis hypersensitivity after chronic stress, accompanied by imbalanced glutamatergic/GABAergic afferent inputs. Moreover, prenatal nicotine exposure enhanced the expression of hippocampal glutamic acid decarboxylase 67 (GAD67), accompanied by a decreased methylation ratio within nt -1019 to -689 of the GAD67 promoter, decreased expression of Dnmt1, and an increased GABA content and density of GABAergic neurons. The fetal rats exhibited changes consistent with the adult rats. Similar effects were also observed by treating the fetal hippocampal cell line H19-7 with 1-100 μM nicotine, while dihydro-β-erythroidine hydrobromide (DHβE), the specific inhibitor of α4β2nAChR, can reverse the effects caused by nicotine. These results indicate that prenatal nicotine exposure can enhance the potential excitability of the hypothalamus via the intrauterine programming of up-regulation of hippocampal GAD67. All of these results contribute to the HPA-axis hypersensitivity in adult offspring.

No abstract

Epidemiological investigations have suggested that periodic use of dexamethasone during pregnancy is a risk factor for abnormal behavior in offspring, but the potential mechanism remains unclear. In this study, we investigated the changes in the glutamatergic system and neurobehavior in female offspring with prenatal dexamethasone exposure (PDE) to explore intrauterine programing mechanisms. Compared with the control group, rat offspring with PDE exhibited spatial memory deficits and anxiety-like behavior. The expression of hippocampal glucocorticoid receptors (GR) and histone deacetylase 2 (HDAC2) increased, whereas histone H3 lysine 14 acetylation (H3K14ac) of brain-derived neurotrophic factor (BDNF) exon IV (BDNF IV) and expression of BDNF decreased. The glutamatergic system also changed. We further observed that changes in the fetal hippocampus were consistent with those in adult offspring. In vitro, the administration of 0.5 μM dexamethasone to the H19-7 fetal hippocampal neuron cells directly led to a cascade of changes in the GR/HDAC2/BDNF pathway, whereas the GR antagonist RU486 and the HDAC2 inhibitor romidepsin (Rom) reversed changes caused by dexamethasone to the H3K14ac level of BDNF IV and to the expression of BDNF. The increase in HDAC2 can be reversed by RU486, and the changes in the glutamatergic system can be partially reversed after supplementation with BDNF. It is suggested that PDE increases the expression of HDAC2 by activating GR, reducing the H3K14ac level of BDNF IV, inducing alterations in neurobehavior and hippocampal glutamatergic system balance. The findings suggest that BDNF supplementation and glutamatergic system improvement are potential therapeutic targets for the fetal origins of abnormal neurobehavior.