BACKGROUND Prenatal stress (PRS) is considered a risk factor for depressive disorder. Adult hippocampal neurogenesis is believed to play a role in the regulation of affective behaviors. GABAergic interneuron is a key modulator in adult hippocampal neurogenesis. Growing evidence indicates that PRS has adverse effects on adult hippocampal neurogenesis and DNA epigenetic modifications of the GABAergic system. The aim of this study was to investigate whether epigenetic GABAergic dysfunction participates in the negative impact of PRS on adult hippocampal neurogenesis and related emotional behaviors. METHODS Behavioral tests were used to explore PRS-induced depression-like behaviors of adult female mice. Immunohistochemistry staining, real-time reverse transcription-polymerase chain reaction, western blot, and chromatin immunoprecipitation were employed to detect adult neurogenesis and epigenetic changes of the GABAergic system in the hippocampus of PRS mice. RESULTS PRS mice developed a depression phenotype accompanied by the inhibited maturation of hippocampal newborn neurons. Compared with control mice, PRS mice showed decreased expression of glutamic acid decarboxylase 67 at the mRNA and protein levels. GABAA receptor agonist phenobarbital could rectify the decrease of 5-bromo-2-deoxyuridine/neuronal nuclei double-positive (BrdU+/NeuN+) cells in PRS mice. PRS mice also showed increased expression of DNA methyltransferase 1 and increased binding of DNA methyltransferase 1 to glutamic acid decarboxylase 67 promoter region. The treatment with DNA methyltransferase 1 inhibitor 5-aza-deoxycytidine restored the decrease of BrdU+/NeuN+ cells and depression-like behaviors in PRS mice via improving GABAergic system. CONCLUSIONS The present results indicate that epigenetic changes of the GABAergic system are responsible for adult hippocampus neurogenesis and depression-like behaviors in PRS mice.

中文翻译：

---

GABA能中间神经元的表观遗传修饰有助于成年海马神经元的发育和产前应激小鼠的抑郁样行为。

背景技术产前压力（PRS）被认为是抑郁症的危险因素。据信成年海马神经发生在调节情感行为中起作用。GABA能中间神经元是成人海马神经发生中的关键调节剂。越来越多的证据表明，PRS对成人海马神经发生和GABA能系统的DNA表观遗传修饰有不利影响。这项研究的目的是调查表观遗传的GABA能功能障碍是否参与了PRS对成人海马神经发生和相关情绪行为的负面影响。方法采用行为测试来探讨PRS诱导的成年雌性小鼠的抑郁样行为。免疫组织化学染色，实时逆转录聚合酶链反应，免疫印迹，采用染色质免疫沉淀法和染色质免疫沉淀法检测PRS小鼠海马的成年神经发生和GABA能系统的表观遗传变化。结果PRS小鼠表现出抑郁型，伴有海马新生神经元成熟受到抑制。与对照小鼠相比，PRS小鼠在mRNA和蛋白质水平上显示出谷氨酸脱羧酶67的表达降低。GABAA受体激动剂苯巴比妥可以纠正PRS小鼠5-溴-2-脱氧尿苷/神经核双阳性（BrdU + / NeuN +）细胞的减少。PRS小鼠还显示出DNA甲基转移酶1的表达增加和DNA甲基转移酶1与谷氨酸脱羧酶67启动子区域的结合增加。DNA甲基转移酶1抑制剂5-氮杂-脱氧胞苷的处理通过改善GABA能系统恢复了PRS小鼠BrdU + / NeuN +细胞的减少和抑郁样行为。结论目前的结果表明，GABA能系统的表观遗传变化是成年海马神经发生和PRS小鼠抑郁样行为的原因。