Corticosterone facilitates fluoxetine-induced neuronal plasticity in the hippocampus.
Corticosterone facilitates fluoxetine-induced neuronal plasticity in the hippocampus.
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DOI：
10.1371/journal.pone.0063662
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Suzuki H
中科院分区：
文献类型：
--
作者：
Kobayashi K;Ikeda Y;Asada M;Inagaki H;Kawada T;Suzuki H
海马齿状回与抗抑郁作用的神经元基础有关。最近，我们已经显示了一种独特的形式的神经元可塑性诱导的多巴胺能抗抑郁药氟西汀，即逆转成熟的成年小鼠的齿状颗粒细胞。这种“去成熟”在大量齿状神经元中诱导，并在氟西汀停药后维持至少一个月，表明去成熟对脑功能的长期强烈影响。然而，可靠的去成熟诱导需要高于小鼠建议的最佳剂量（10 - 18 mg/kg/天）的氟西汀剂量，这对该效应的临床相关性提出了质疑。由于我们以前的研究是在幼稚小鼠中进行的，在本研究中，我们使用慢性皮质酮治疗的小鼠模型（与抑郁症相关的神经内分泌病理生理学）重新检查氟西汀的作用。在皮质酮处理的小鼠中，氟西汀以10 mg/kg/天剂量下调成熟颗粒细胞标志物的表达，并减弱颗粒细胞轴突苔藓纤维形成的突触处的强频率易化，表明诱导颗粒细胞去成熟。此外，氟西汀引起苔藓纤维突触的多巴胺能调制的显着增强。然而，在溶剂处理的小鼠中，该剂量的氟西汀没有显著影响。氟西汀的血浆水平与长期服用氟西汀的患者相当，皮质酮并不影响它。这些结果表明，皮质酮促进氟西汀诱导的齿状颗粒细胞的可塑性变化。我们的发现可能提供深入了解神经元机制增强抗抑郁药物在某些病理条件下的反应。
The hippocampal dentate gyrus has been implicated in a neuronal basis of antidepressant action. We have recently shown a distinct form of neuronal plasticity induced by the serotonergic antidepressant fluoxetine, that is, a reversal of maturation of the dentate granule cells in adult mice. This “dematuration” is induced in a large population of dentate neurons and maintained for at least one month after withdrawal of fluoxetine, suggesting long-lasting strong influence of dematuration on brain functioning. However, reliable induction of dematuration required doses of fluoxetine higher than suggested optimal doses for mice (10 to 18 mg/kg/day), which casts doubt on the clinical relevance of this effect. Since our previous studies were performed in naive mice, in the present study, we reexamined effects of fluoxetine using mice treated with chronic corticosterone that model neuroendocrine pathophysiology associated with depression. In corticosterone-treated mice, fluoxetine at 10 mg/kg/day downregulated expression of mature granule cell markers and attenuated strong frequency facilitation at the synapse formed by the granule cell axon mossy fiber, suggesting the induction of granule cell dematuration. In addition, fluoxetine caused marked enhancement of dopaminergic modulation at the mossy fiber synapse. In vehicle-treated mice, however, fluoxetine at this dose had no significant effects. The plasma level of fluoxetine was comparable to that in patients taking chronic fluoxetine, and corticosterone did not affect it. These results indicate that corticosterone facilitates fluoxetine-induced plastic changes in the dentate granule cells. Our finding may provide insight into neuronal mechanisms underlying enhanced responsiveness to antidepressant medication in certain pathological conditions.
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