Neurotrophic-priming of glucocorticoid receptor signaling is essential for neuronal plasticity to stress and antidepressant treatment
Neurotrophic-priming of glucocorticoid receptor signaling is essential for neuronal plasticity to stress and antidepressant treatment
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DOI：
10.1073/pnas.1509045112
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发表时间：
2015-12-22
影响因子：
11.1
通讯作者：
Jeanneteau, Freddy
中科院分区：
文献类型：
--
作者：
Arango-Lievano, Margarita;Lambert, W. Marcus;Jeanneteau, Freddy
神经营养因子和糖皮质激素是强大的突触修饰剂，其活性失调是发展压力相关疾病的危险因素。低水平的脑源性神经营养因子（BDNF）增加糖皮质激素受体（GR）的脱敏和对压力的脆弱性，而较高水平的BDNF促进GR介导的信号传导和对抗抑郁药的反应。然而，GR功能的神经营养启动的分子机制还知之甚少.在这里，我们提供的证据表明，激活的TrkB-MAPK通路，当配对的GR-蛋白磷酸酶5通路的失活，导致持续的GR磷酸化在BDNF敏感的网站，是必不可少的神经元可塑性基因的转录。在体内破坏GR磷酸化或TrkB信号传导的遗传策略损害了慢性应激的神经可塑性和抗抑郁药氟西汀的作用。我们的研究结果表明，BDNF和糖皮质激素的协调作用，促进神经元的可塑性，并在任何一个途径的中断可以设置阶段的发展压力诱导的精神疾病。
Neurotrophins and glucocorticoids are robust synaptic modifiers, and deregulation of their activities is a risk factor for developing stress-related disorders. Low levels of brain-derived neurotrophic factor (BDNF) increase the desensitization of glucocorticoid receptors (GR) and vulnerability to stress, whereas higher levels of BDNF facilitate GR-mediated signaling and the response to antidepressants. However, the molecular mechanism underlying neurotrophic- priming of GR function is poorly understood. Here we provide evidence that activation of a TrkB-MAPK pathway, when paired with the deactivation of a GR-protein phosphatase 5 pathway, resulted in sustained GR phosphorylation at BDNF-sensitive sites that is essential for the transcription of neuronal plasticity genes. Genetic strategies that disrupted GR phosphorylation or TrkB signaling in vivo impaired the neuroplasticity to chronic stress and the effects of the antidepressant fluoxetine. Our findings reveal that the coordinated actions of BDNF and glucocorticoids promote neuronal plasticity and that disruption in either pathway could set the stage for the development of stress-induced psychiatric diseases.