King's College London, Institute of Psychiatry, Section of Perinatal Psychiatry and Stress, Psychiatry and Immunology (SPI-lab), Department of Psychological Medicine, London, UK.
Mol Psychiatry. 2011 Jul;16(7):738-50. doi: 10.1038/mp.2011.26. Epub 2011 Apr 12.
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, p27(Kip1) and p57(Kip2). 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.
抗抑郁药可增加动物模型中的成年海马神经发生，但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来研究参与抗抑郁药调节神经发生的分子途径。因为我们之前的研究表明，抗抑郁药调节糖皮质激素受体（GR）的功能，所以我们特别测试了 GR 是否可能参与这些药物对神经发生的影响。我们发现，抗抑郁药舍曲林（sertraline）的治疗（3-10 天）通过一种 GR 依赖性机制增加了神经元分化。具体而言，舍曲林增加了不成熟的、双皮质素（Dcx）阳性的神经前体细胞（增加 16%）和成熟的、微管相关蛋白-2（MAP2）阳性的神经元（增加 26%）。这一作用被 GR 拮抗剂 RU486 所消除。有趣的是，通过 5'-溴脱氧尿苷（BrdU）掺入研究的祖细胞增殖，仅在细胞与舍曲林和 GR 激动剂地塞米松共同处理时才增加（增加 14%），这一作用也被 RU486 消除。此外，磷酸二酯酶 4（PDE4）抑制剂 rolipram 增强了舍曲林的作用，而蛋白激酶 A（PKA）抑制剂 H89 则抑制了舍曲林的作用。事实上，舍曲林增加了 GR 的转录激活，改变了 GR 的磷酸化，并增加了 GR 调节的细胞周期蛋白依赖性激酶-2（CDK2）抑制剂 p27（Kip1）和 p57（Kip2）的表达。总之，我们的数据表明，抗抑郁药舍曲林通过一种需要 PKA 信号、GR 磷酸化和特定基因激活的 GR 依赖性机制增加了人海马神经发生。我们的数据表明，GR 在抗抑郁药诱导的人类神经发生调节中起着重要作用。
