Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institute, Stockholm, Sweden.
Int J Neuropsychopharmacol. 2012 Jun;15(5):669-79. doi: 10.1017/S1461145711000940. Epub 2011 Jun 20.
P11 (S100A10) has been associated with the pathophysiology of depression both in human and rodent models. Different types of antidepressants have been shown to increase P11 levels in distinct brain regions and P11 gene therapy was recently proven effective in reversing depressive-like behaviours in mice. However, the molecular mechanisms that govern P11 gene expression in response to antidepressants still remain elusive. In this study we report decreased levels of P11, associated with higher DNA methylation in the promoter region, in the prefrontal cortex of the Flinders Sensitive Line (FSL) genetic rodent model of depression. This hypermethylated pattern was reversed to normal, as indicated by the control line, after chronic administration of escitalopram (a selective serotonin reuptake inhibitor; SSRI). The escitalopram-induced hypomethylation was associated with both an increase in P11 gene expression and a reduction in mRNA levels of two DNA methyltransferases that have been shown to maintain DNA methylation in adult forebrain neurons (Dnmt1 and Dnmt3a). In conclusion, our data further support a role for P11 in depression-like states and suggest that this gene is controlled by epigenetic mechanisms that can be affected by antidepressant treatment.
P11（S100A10）与人类和啮齿动物模型中的抑郁症的病理生理学有关。不同类型的抗抑郁药已被证明可增加不同脑区的 P11 水平，最近的 P11 基因治疗已被证明可有效逆转小鼠的抑郁样行为。然而，调控抗抑郁药反应中 P11 基因表达的分子机制仍不清楚。在这项研究中，我们报告了抑郁的弗林德斯敏感系（FSL）遗传啮齿动物模型前额叶皮层中 P11 水平降低，与启动子区域的 DNA 高甲基化有关。这种超甲基化模式在慢性给予艾司西酞普兰（一种选择性 5-羟色胺再摄取抑制剂；SSRI）后恢复正常，与对照系一致。艾司西酞普兰诱导的低甲基化与 P11 基因表达的增加以及已显示在成年前脑神经元中维持 DNA 甲基化的两种 DNA 甲基转移酶（Dnmt1 和 Dnmt3a）的 mRNA 水平降低有关。总之，我们的数据进一步支持 P11 在抑郁样状态中的作用，并表明该基因受表观遗传机制调控，可受抗抑郁治疗的影响。
