Samuels Benjamin Adam, Anacker Christoph, Hu Alice, Levinstein Marjorie R, Pickenhagen Anouchka, Tsetsenis Theodore, Madroñal Noelia, Donaldson Zoe R, Drew Liam John, Dranovsky Alex, Gross Cornelius T, Tanaka Kenji F, Hen René
Department of Psychiatry, Columbia University Medical Center and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, New York, USA.
Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
Nat Neurosci. 2015 Nov;18(11):1606-16. doi: 10.1038/nn.4116. Epub 2015 Sep 21.
Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants, but the mechanisms by which they influence behavior are only partially resolved. Adult hippocampal neurogenesis is necessary for some of the responses to SSRIs, but it is not known whether mature dentate gyrus granule cells (DG GCs) also contribute. We deleted the serotonin 1A receptor (5HT1AR, a receptor required for the SSRI response) specifically from DG GCs and found that the effects of the SSRI fluoxetine on behavior and the hypothalamic-pituitary-adrenal (HPA) axis were abolished. By contrast, mice lacking 5HT1ARs only in young adult-born GCs (abGCs) showed normal fluoxetine responses. Notably, 5HT1AR-deficient mice engineered to express functional 5HT1ARs only in DG GCs responded to fluoxetine, indicating that 5HT1ARs in DG GCs are sufficient to mediate an antidepressant response. Taken together, these data indicate that both mature DG GCs and young abGCs must be engaged for an antidepressant response.
选择性5-羟色胺再摄取抑制剂（SSRIs）是广泛使用的抗抑郁药，但其影响行为的机制仅部分得到解析。成年海马神经发生对于某些对SSRIs的反应是必要的，但尚不清楚成熟的齿状回颗粒细胞（DG GCs）是否也有作用。我们特异性地从DG GCs中删除了5-羟色胺1A受体（5HT1AR，一种SSRIs反应所需的受体），发现SSRI氟西汀对行为和下丘脑-垂体-肾上腺（HPA）轴的作用被消除。相比之下，仅在年轻的成年新生颗粒细胞（abGCs）中缺乏5HT1ARs的小鼠对氟西汀的反应正常。值得注意的是，经过基因改造仅在DG GCs中表达功能性5HT1ARs的5HT1AR缺陷小鼠对氟西汀有反应，这表明DG GCs中的5HT1ARs足以介导抗抑郁反应。综上所述，这些数据表明，成熟的DG GCs和年轻的abGCs都必须参与才能产生抗抑郁反应。
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