Estrogen receptor β deficiency impairs BDNF-5-HT(2A) signaling in the hippocampus of female brain: A possible mechanism for menopausal depression.
Estrogen receptor β deficiency impairs BDNF-5-HT(2A) signaling in the hippocampus of female brain: A possible mechanism for menopausal depression.
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DOI：
10.1016/j.psyneuen.2017.05.016
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发表时间：
2017-08
影响因子：
3.7
通讯作者：
Zhao L
中科院分区：
文献类型：
--
作者：
Chhibber A;Woody SK;Karim Rumi MA;Soares MJ;Zhao L
目前，全世界有3.5亿人患有抑郁症，美国每年有1900万人患有抑郁症。女性患严重抑郁症的可能性是男性的2.5倍，一些女性在更年期过渡期间的风险似乎更高。雌激素信号与包括抑郁在内的情绪障碍的病理生理学有关；然而，其潜在的机制却知之甚少。本研究探讨雌激素受体亚型ER-α和ER-β在脑源性神经营养因子和5-羟色胺信号转导中的作用。在ERα-/-和ERβ-/-小鼠模型中的分析表明，脑源性神经营养因子在ERβ-/-小鼠中显著下调，但在ERα-/-小鼠中没有下调，并且ERβ-/-介导的效应是脑区特有的。在ERβ-/-小鼠的海马区，脑源性神经营养因子的蛋白表达降低了40%；相比之下，脑源性神经营养因子在皮质和下丘脑中的表达变化幅度要小得多，而且不显著。对原代海马神经元的进一步分析表明，ERβ激动剂显著增强了脑源性神经营养因子/trkB信号通路，其下游信号通路参与了突触的可塑性。随后在ERβ突变大鼠模型中的研究表明，ERβ的破坏与大鼠海马5-HT2A水平的显著升高有关，但与5-HT1A的水平无关，表明ERβ对5-HT2A具有负性调节作用。在原代神经元培养中的进一步分析表明，BDNF和5-HT2A通路之间存在显著的关联，并且数据显示TrkB的激活下调了5-HT2A，而5-HT2A的激活对BDNF没有影响，表明BDNF/TrkB是5-HT2A通路的上游调节因子。综上所述，这些发现暗示绝经期间雌激素稳态的破坏导致BDNF-5-HT2A信号的失调和突触可塑性的减弱，这些共同作用使大脑容易处于抑郁的脆弱状态。及时干预ER-β靶向调节剂可能会减弱这种易感性，降低风险或改善这种脑部疾病的临床表现。
Depression currently affects 350 million people worldwide and 19 million Americans each year. Women are 2.5 times more likely to experience major depression than men, with some women appearing to be at a heightened risk during the menopausal transition. Estrogen signaling has been implicated in the pathophysiology of mood disorders including depression; however, the underlying mechanisms are poorly understood. In this study, the role of estrogen receptor (ER) subtypes, ERα and ERβ, in the regulation of brain-derived neurotrophic factor (BDNF) and serotonin (5-HT) signaling was investigated; two pathways that have been hypothesized to be interrelated in the etiology of depression. The analyses in ERα-/- and ERβ-/- mouse models demonstrated that BDNF was significantly downregulated in ERβ-/- but not ERα-/- mice, and the ERβ-/--mediated effect was brain-region specific. A 40% reduction in BDNF protein expression was found in the hippocampus of ERβ-/- mice; in contrast, the changes in BDNF were at a much smaller magnitude and insignificant in the cortex and hypothalamus. Further analyses in primary hippocampal neurons indicated that ERβ agonism significantly enhanced BDNF/TrkB signaling and the downtream cascades involved in synaptic plasticity. Subsequent study in ERβ mutant rat models demonstrated that disruption of ERβ was associated with a significantly elevated level of 5-HT2A but not 5-HT1A in rat hippocampus, indicating ERβ negatively regulates 5-HT2A. Additional analyses in primary neuronal cultures revealed a significant association between BDNF and 5-HT2A pathways, and the data showed that TrkB activation downregulated 5-HT2A whereas activation of 5-HT2A had no effect on BDNF, suggesting that BDNF/TrkB is an upstream regulator of the 5-HT2A pathway. Collectively, these findings implicate that the disruption in estrogen homeostasis during menopause leads to dysregulation of BDNF–5-HT2A signaling and weakened synaptic plasticity, which together predispose the brain to a vulnerable state for depression. Timely intervention with an ERβ-targeted modulator could potentially attenuate this susceptibility and reduce the risk or ameliorate the clinical manifestation of this brain disorder.
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DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
影响因子：
3.7
作者：
O'Leary, Olivia F.;Wu, Xuefei;Castren, Eero
通讯作者：
Castren, Eero
影响因子：
6
作者：
Rush, A. John;Warden, Diane;Nierenberg, Andrew A.
通讯作者：
Nierenberg, Andrew A.
影响因子：
11
作者：
Frazer, A;Benmansour, S
通讯作者：
Benmansour, S
影响因子：
16.2
作者：
ERNFORS, P;WETMORE, C;PERSSON, H
通讯作者：
PERSSON, H