Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor.
Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor.
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DOI：
10.1038/mp.2011.26
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发表时间：
2011-07
影响因子：
11
通讯作者：
Pariante, C. M.
中科院分区：
文献类型：
--
作者：
Anacker, C.;Zunszain, P. A.;Cattaneo, A.;Carvalho, L. A.;Garabedian, M. J.;Thuret, S.;Price, J.;Pariante, C. M.
抗抑郁药在动物模型中增加成年海马神经发生，但其潜在的分子机制尚不清楚。在这项研究中，我们使用人海马祖细胞研究参与抗抑郁药诱导的神经发生调制的分子途径。由于我们以前的研究表明，抗抑郁药调节糖皮质激素受体（GR）的功能，我们专门测试了GR是否可能参与这些药物对神经发生的影响。我们发现，治疗（3-10天）与抗抑郁药，舍曲林，增加神经元分化通过GR依赖性机制。具体而言，舍曲林增加了未成熟的双皮质素（Dcx）阳性神经母细胞（+16%）和成熟的微管蛋白相关蛋白-2（MAP 2）阳性神经元（+26%）。GR-拮抗剂RU 486可消除这种作用。有趣的是，通过5′-溴脱氧尿苷（BrdU）掺入研究的祖细胞增殖仅在细胞用舍曲林和GR激动剂地塞米松共同处理时增加（+14%），这种作用也被RU 486消除。此外，磷酸二酯酶4型（PDE 4）抑制剂咯利普兰增强舍曲林的作用，而蛋白激酶A（PKA）抑制剂H89抑制舍曲林的作用。事实上，舍曲林增加了GR反式激活，改变了GR磷酸化，并增加了GR调节的细胞周期蛋白依赖性激酶2（CDK 2）抑制剂p27 Kip 1和p57 Kip 2的表达。总之，我们的数据表明，抗抑郁药，舍曲林，增加人类海马神经通过GR依赖性机制，需要PKA信号，GR磷酸化和激活一组特定的基因。我们的数据指向GR在抗抑郁药诱导的人类神经发生调节中的重要作用。
Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. In this study, we used human hippocampal progenitor cells to investigate the molecular pathways involved in the antidepressant-induced modulation of neurogenesis. Because our previous studies have shown that antidepressants regulate glucocorticoid receptor (GR) function, we specifically tested whether the GR may be involved in the effects of these drugs on neurogenesis. We found that treatment (for 3–10 days) with the antidepressant, sertraline, increased neuronal differentiation via a GR-dependent mechanism. Specifically, sertraline increased both immature, doublecortin (Dcx)-positive neuroblasts (+16%) and mature, microtubulin-associated protein-2 (MAP2)-positive neurons (+26%). This effect was abolished by the GR-antagonist, RU486. Interestingly, progenitor cell proliferation, as investigated by 5′-bromodeoxyuridine (BrdU) incorporation, was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone, (+14%) an effect which was also abolished by RU486. Furthermore, the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram, enhanced the effects of sertraline, whereas the protein kinase A (PKA)-inhibitor, H89, suppressed the effects of sertraline. Indeed, sertraline increased GR transactivation, modified GR phosphorylation and increased expression of the GR-regulated cyclin-dependent kinase-2 (CDK2) inhibitors, p27Kip1 and p57Kip2. In conclusion, our data suggest that the antidepressant, sertraline, increases human hippocampal neurogenesis via a GR-dependent mechanism that requires PKA signaling, GR phosphorylation and activation of a specific set of genes. Our data point toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans.
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影响因子：
11
作者：
Bessa, J. M.;Ferreira, D.;Sousa, N.
通讯作者：
Sousa, N.
影响因子：
3.7
作者：
Anacker, Christoph;Zunszain, Patricia A.;Carvalho, Livia A.;Pariante, Carmine M.
通讯作者：
Pariante, Carmine M.
影响因子：
30.8
作者：
Binder, EB;Salyakina, D;Muller-Myhsok, B
通讯作者：
Muller-Myhsok, B
影响因子：
3.5
作者：
Duman, RS
通讯作者：
Duman, RS
影响因子：
5.6
作者：
Carvalho, L. A.;Garner, B. A.;Dew, T.;Fazakerley, H.;Pariante, C. M.
通讯作者：
Pariante, C. M.