The roles of BDNF, pCREB and Wnt3a in the latent period preceding activation of progenitor cell mitosis in the adult dentate gyrus by fluoxetine.
The roles of BDNF, pCREB and Wnt3a in the latent period preceding activation of progenitor cell mitosis in the adult dentate gyrus by fluoxetine.
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DOI：
10.1371/journal.pone.0013652
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发表时间：
2010-10-27
期刊：
影响因子：
3.7
通讯作者：
Herbert J
中科院分区：
文献类型：
--
作者：
Pinnock SB;Blake AM;Platt NJ;Herbert J
与许多其他物种一样，大鼠海马齿状回中新神经元的形成持续到成年。神经发生本身被证明是高度不稳定的，并且受到许多因素的调节。其中之一是血清素能系统：药物治疗（例如SSRI氟西汀）显着刺激齿状回祖细胞的有丝分裂。但这个过程有一个显著的功能：至少需要连续治疗14天才能见效。尽管氟西汀的药理作用发生在首次给药后1小时左右。本文探讨了BDNF在这一过程中的作用，使用Trk拮抗剂（K252a）的有丝分裂标记Ki67和相关的表达pCREB和Wnt3a的祖细胞标记的效果。这些实验显示（i）氟西汀增加齿状回中的Ki67计数以及pCREB和Wnt3a表达。氟西汀对祖细胞和pCREB（但不是Wnt3a）的作用取决于Trk受体激活，因为它被icv输注K252a阻止。(ii)氟西汀作用的前7天（在此期间，祖细胞有丝分裂没有明显变化）以及后7天都需要这些受体。增加pCREB总是与祖细胞有丝分裂，但Wnt3a表达可能是必要的，但不足以增加祖细胞增殖。这些结果揭示了氟西汀对成年齿状回神经发生的作用，具有临床和实验意义。
The formation of new neurons continues into adult life in the dentate gyrus of the rat hippocampus, as in many other species. Neurogenesis itself turns out to be highly labile, and is regulated by a number of factors. One of these is the serotoninergic system: treatment with drugs (such as the SSRI fluoxetine) markedly stimulates mitosis in the progenitor cells of the dentate gyrus. But this process has one remarkable feature: it takes at least 14 days of continuous treatment to be effective. This is despite the fact that the pharmacological action of fluoxetine occurs within an hour or so of first administration. This paper explores the role of BDNF in this process, using the effect of a Trk antagonist (K252a) on the labelling of progenitor cells with the mitosis marker Ki67 and the associated expression of pCREB and Wnt3a. These experiments show that (i) Fluoxetine increased Ki67 counts, as well as pCREB and Wnt3a expression in the dentate gyrus. The action of fluoxetine on the progenitor cells and on pCREB (but not Wnt3a) depends upon Trk receptor activation, since it was prevented by icv infusion of K252a. (ii) These receptors are required for both the first 7 days of fluoxetine action, during which no apparent change in progenitor mitosis occurs, as well as the second 7 days. Increased pCREB was always associated with progenitor cell mitosis, but Wnt3a expression may be necessary but not sufficient for increased progenitor cell proliferation. These results shed new light on the action of fluoxetine on neurogenesis in the adult dentate gyrus, and have both clinical and experimental interest.
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