Role of epigenetics on long-lasting behavioral and gene-expression changes following neonate exposure to antidepressants

摘要 抑郁和焦虑在怀孕期间很普遍，通常用5-羟色胺选择性治疗。 再摄取抑制剂（SSRI）抗抑郁药。这些药物自由地从母体传递到胎盘， 发育中的胎儿中的肾上腺素能稳态。然而，血清素作为一种营养因子， 胚胎发育，并在中枢神经系统的结构发育中起重要作用， 导致了许多研究调查对胎儿的短期和长期影响。多种啮齿类动物 模型表明，新生儿在发育敏感的时间范围内暴露于SSRIs， 相当于人类怀孕的第三个三个月导致与以下相关的长期行为变化： 焦虑和抑郁在没有持续暴露于SSRI的情况下， 表明药物通过表观遗传机制对发育产生影响。本研究将 通过使用一种携带突变型5-羟色胺转运蛋白的新型转基因小鼠来研究这一假设 使小鼠对许多SSRI不敏感，同时保持正常的5-羟色胺转运蛋白， 体内平衡小鼠将被评估基因表达，表观遗传标记和行为的变化， SSRI治疗和/或作为成年动物。SSRI不敏感小鼠将提供关键控制，以消除 背景效应，并查明这一现象背后的相关目标。识别出的目标可以 在人群中进行探索，目的是提供对SSRI相关风险的清晰理解- 怀孕期间的治疗。

ABSTRACT Depression and anxiety are prevalent during pregnancy and commonly treated with serotonin selective reuptake inhibitor (SSRI) antidepressants. These drugs pass freely from mother to placenta and alter the serotonergic homeostasis in the developing fetus. However, serotonin acts as a trophic factor during embryogenesis and plays an important role in structural development of the central nervous system which has led to a number of studies investigating the short and long-term consequences to the fetus. Multiple rodent models have demonstrated that neonate exposure to SSRIs during a developmentally sensitive time frame equivalent to the 3rd trimester of human pregnancy leads to long-lasting behavioral changes associated with anxiety and depression. These behavioral outcomes in the absence of continued exposure to the SSRI suggests a drug-mediated impact on development through an epigenetic mechanism. This study will investigate this assumption through use a novel transgenic mouse that harbors a mutant serotonin transporter that renders the mouse insensitive to many SSRIs while maintaining normal serotonin transporter and homeostasis. Mice will be evaluated for changes in gene expression, epigenetic marks, and behavior just after SSRI treatment and/or as adult animals. The SSRI-insensitive mouse will provide a critical control to eliminate background effects and pinpoint relevant targets that underlie this phenomenon. Identified targets can then be explored in human populations with the intent of providing a clear understanding of risks involved with SSRI- treatment during pregnancy.