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Jmjd3 is involved in the susceptibility to depression induced by maternal separation via enhancing the neuroinflammation in the prefrontal cortex and hippocampus of male rats.
Experimental Neurology ( IF 4.6 ) Pub Date : 2020-02-18 , DOI: 10.1016/j.expneurol.2020.113254
Rui Wang 1 , Wei Wang 1 , Jingjing Xu 1 , Dexiang Liu 1 , Huiran Wu 1 , Xiaqing Qin 1 , Hong Jiang 1 , Fang Pan 1
Affiliation  

Adverse childhood experience is a major risk factor for the onset of depression in adulthood. Neuroinflammation characterized by microglial activation and cytokine secretion is involved in susceptibility to depression induced by early life stress. Jumonji domain-containing protein 3 (Jmjd3), a trimethylated lysine 27 in histone 3 (H3K27me3) demethylase, can be activated by nuclear factor-kappa B (NF-κB), further regulating the expression of pro-inflammatory cytokines and resulting in neuroinflammation. However, its involvement in susceptibility to early life stress-related depression is unknown. In the current study, maternal separation (MS) was utilized as a model of early life stress and systemic lipopolysaccharide (LPS) administration in adulthood was used as a later-life challenge. Depressive- and anxiety-like behaviors and memory impairment were detected by behavioral tests. Microglial activation, pro-inflammatory cytokine expression, and NF-κB, Jmjd3, and H3K27me3 expression were detected in the prefrontal cortex and hippocampus in both infant and adult rats. Meanwhile, the Jmjd3 inhibitor GSK-J4 was used as an intervention in vivo and in vitro. Our results showed that MS induced depression-like behaviors and synchronously caused microglial activation, pro-inflammatory cytokine over-expression, NF-κB and Jmjd3 over-expression, and decreased H3K27me3 expression in infant rats. All these alterations could also be detected in adulthood. Seven-day LPS administration in adult rats induced similar changes of behaviors and biomarkers. Interestingly, compared with rats not exposed to MS, MS-exposed rats receiving LPS administration developed more severe depression-like behaviors and neuroinflammatory status, higher levels of NF-κB and Jmjd3 expression, and lower levels of H3K27me3 expression. In addition, LPS induced microglial activation, pro-inflammatory cytokine expression and increased Jmjd3 expression in vitro. Furthermore, GSK-J4 treatment alleviated these alterations in vivo and in vitro. Thus, our data indicate that Jmjd3 is involved in the susceptibility to depression induced by MS via enhancement of neuroinflammation in the prefrontal cortex and hippocampus of rats.

中文翻译:

Jmjd3通过增强雄性大鼠前额叶皮层和海马的神经炎症而参与母体分离引起的抑郁症易感性。

童年时期的不良经历是成年后抑郁发作的主要危险因素。以小胶质细胞活化和细胞因子分泌为特征的神经炎症与生活压力引起的抑郁症易感性有关。含有Jumonji域的蛋白质3(Jmjd3)是组蛋白3(H3K27me3)去甲基化酶中的三甲基赖氨酸27,可被核因子-κB(NF-κB)激活,进一步调节促炎性细胞因子的表达并导致神经炎症。然而,其参与早期生活压力相关性抑郁症易感性的原因尚不清楚。在当前的研究中,母体分离(MS)被用作早期生活压力的模型,成年期全身性脂多糖(LPS)的给药被用于后期生活的挑战。通过行为测试检测到抑郁和焦虑样行为以及记忆障碍。在幼年和成年大鼠的前额叶皮层和海马中均检测到小胶质细胞激活,促炎性细胞因子表达以及NF-κB,Jmjd3和H3K27me3表达。同时,Jmjd3抑制剂GSK-J4被用作体内和体外干预。我们的研究结果表明,MS诱导了类似抑郁症的行为,并同时引起小胶质细胞活化,促炎性细胞因子过表达,NF-κB和Jmjd3过表达,以及H3K27me3表达降低。所有这些变化也可以在成年期发现。成年大鼠服用LPS 7天后,其行为和生物标志物也发生了类似的变化。有趣的是,与未接触MS的大鼠相比,接受LPS给药的MS暴露大鼠表现出更严重的抑郁样行为和神经炎症状态,NF-κB和Jmjd3表达水平更高,H3K27me3表达水平更低。另外,LPS在体外诱导小胶质细胞活化,促炎性细胞因子表达和Jmjd3表达增加。此外,GSK-J4处理可减轻体内和体外的这些变化。因此,我们的数据表明Jmjd3通过增强大鼠前额叶皮层和海马中的神经炎症而参与了MS诱发的抑郁症易感性。促炎性细胞因子表达和体外Jmjd3表达增加。此外,GSK-J4处理可减轻体内和体外的这些变化。因此,我们的数据表明Jmjd3通过增强大鼠前额叶皮层和海马中的神经炎症而参与了MS诱发的抑郁症易感性。促炎性细胞因子表达和体外Jmjd3表达增加。此外,GSK-J4处理可减轻体内和体外的这些变化。因此,我们的数据表明Jmjd3通过增强大鼠前额叶皮层和海马中的神经炎症而参与了MS诱发的抑郁症易感性。
更新日期:2020-02-20
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