Department of Pharmacology, Graduate School of Medicine, Nippon Medical School, Bunkyo-ku, Tokyo, Japan.
PLoS One. 2013 May 10;8(5):e63662. doi: 10.1371/journal.pone.0063662. Print 2013.
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.
海马齿状回参与了抗抑郁药作用的神经基础。我们最近发现了一种由血清素能抗抑郁药氟西汀诱导的独特形式的神经元可塑性，即成年小鼠齿状颗粒细胞的成熟逆转。这种“去成熟”是在大量齿状神经元中诱导的，并在氟西汀停药后至少维持一个月，表明去成熟对大脑功能有持久的强烈影响。然而，可靠地诱导去成熟需要的氟西汀剂量高于建议的小鼠最佳剂量（10 至 18 毫克/千克/天），这使人对这种效应的临床相关性产生了怀疑。由于我们之前的研究是在未处理的小鼠中进行的，因此在本研究中，我们使用用慢性皮质酮处理的小鼠重新检查了氟西汀的作用，这种方法模拟了与抑郁相关的神经内分泌病理生理学。在皮质酮处理的小鼠中，氟西汀 10 毫克/千克/天可下调成熟颗粒细胞标志物的表达，并减弱颗粒细胞轴苔藓纤维形成的突触的强频率易化，表明颗粒细胞去成熟的诱导。此外，氟西汀导致苔藓纤维突触多巴胺能调节明显增强。然而，在载体处理的小鼠中，该剂量的氟西汀没有显著作用。氟西汀的血浆水平与接受慢性氟西汀治疗的患者相当，皮质酮对其没有影响。这些结果表明，皮质酮促进了氟西汀诱导的齿状颗粒细胞中的可塑性变化。我们的发现可能为增强对某些病理条件下抗抑郁药物反应的神经元机制提供了新的认识。
