Adolescent Fluoxetine Exposure Induces Persistent Gene Expression Changes in the Hippocampus of Adult Male C57BL/6 Mice.
Adolescent Fluoxetine Exposure Induces Persistent Gene Expression Changes in the Hippocampus of Adult Male C57BL/6 Mice.
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青春期氟西汀暴露诱导成年雄性C57BL/6小鼠海马区持续性基因表达的变化
DOI：
10.1007/s12035-020-02221-9
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发表时间：
2021-04
影响因子：
5.1
通讯作者：
Lira O
中科院分区：
文献类型：
--
作者：
Iñiguez SD;Flores-Ramirez FJ;Themann A;Lira O
与情绪有关的疾病在儿童和青少年中的发病率很高，由于对这些年轻人的不利影响，构成了公共卫生挑战。用选择性5-羟色胺再摄取抑制剂氟西汀（FLX）治疗是对患有情感相关疾病的儿科患者进行药物干预的第一线。虽然这种抗抑郁药的使用被认为在青少年人群中有效，但青少年FLX暴露的持久神经生物学后果尚未得到充分了解。因此，我们探讨了持久的分子适应，在成年海马，作为青少年FLX预处理的功能。为此，我们在青春期（出生后[PD] 35-49天）对雄性C57 BL/6小鼠给予FLX（20 mg/kg/天）。在21天的洗脱期（PD 70）后，解剖整个海马组织。然后，我们使用qPCR分析来评估与主要细胞内信号转导途径相关的基因表达的变化，包括细胞外信号调节激酶（ERK）、磷脂酰肌醇-3-激酶（PI 3 K）/AKT途径和无翅（Wnt）-杂乱-GSK 3B信号级联。我们的研究结果表明，FLX处理导致ERK、PI 3 K/AKT和Wnt细胞内信号传导途径中许多基因的mRNA水平长期失调，沿着转录因子CREB、ΔFosB和Zif 268的增加。最后，FLX处理导致与细胞骨架完整性（β-肌动蛋白）和半胱天冬酶激活（DIABLO）相关的转录物持续增加，同时减少与代谢（岩藻糖激酶）和整体神经元激活（c-Fos）相关的基因。总的来说，这些数据表明，青少年FLX暴露介导了成年期海马基因表达的持续变化，因此，质疑早期暴露于这种抗抑郁药物的安全性。
Mood-related disorders have a high prevalence among children and adolescents, posing a public health challenge, given their adverse impact on these young populations. Treatment with the selective serotonin reuptake inhibitor fluoxetine (FLX) is the first line of pharmacological intervention in pediatric patients suffering from affect-related illnesses. Although the use of this antidepressant has been deemed efficacious in the juvenile population, the enduring neurobiological consequences of adolescent FLX exposure are not well understood. Therefore, we explored for persistent molecular adaptations, in the adult hippocampus, as a function of adolescent FLX pretreatment. To do this, we administered FLX (20 mg/kg/day) to male C57BL/6 mice during adolescence (postnatal day [PD] 35–49). After a 21-day washout period (PD70), whole hippocampal tissue was dissected. We then used qPCR analysis to assess changes in the expression of genes associated with major intracellular signal transduction pathways, including the extracellular signal-regulated kinase (ERK), the phosphatidylinositide-3-kinase (PI3K)/AKT pathway, and the wingless (Wnt)-dishevelled-GSK3B signaling cascade. Our results show that FLX treatment results in long-term dysregulation of mRNA levels across numerous genes from the ERK, PI3K/AKT, and Wnt intracellular signaling pathways, along with increases of the transcription factors CREB, ΔFosB, and Zif268. Lastly, FLX treatment resulted in persistent increases of transcripts associated with cytoskeletal integrity (β-actin) and caspase activation (DIABLO), while decreasing genes associated with metabolism (fucose kinase) and overall neuronal activation (c-Fos). Collectively, these data indicate that adolescent FLX exposure mediates persistent alterations in hippocampal gene expression in adulthood, thus, questioning the safety of early-life exposure to this antidepressant medication.
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影响因子：
2.7
作者：
Freitas, Andiara E.;Machado, Daniele G.;Rodrigues, Ana Lucia S.
通讯作者：
Rodrigues, Ana Lucia S.
影响因子：
3.4
作者：
Alcantara LF;Warren BL;Parise EM;Iñiguez SD;Bolaños-Guzmán CA
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Bolaños-Guzmán CA
影响因子：
6.6
作者：
Flores-Ramirez, Francisco J.;Parise, Lyonna F.;Iniguez, Sergio D.
通讯作者：
Iniguez, Sergio D.
影响因子：
3.3
作者：
Dale E;Pehrson AL;Jeyarajah T;Li Y;Leiser SC;Smagin G;Olsen CK;Sanchez C
通讯作者：
Sanchez C
影响因子：
2.7
作者：
Fosnocht AQ;Lucerne KE;Ellis AS;Olimpo NA;Briand LA
通讯作者：
Briand LA