From the Department of Neuroscience, Ottawa Hospital Research Institute, UOttawa Brain and Mind Research Institute, Ottawa, Ont., Canada.
J Psychiatry Neurosci. 2019 May 1;44(3):164-176. doi: 10.1503/jpn.180209.
Major depression and anxiety are highly prevalent and involve chronic dysregulation of serotonin, but they remain poorly understood. Here, we review novel transcriptional (genetic, epigenetic) and posttranscriptional (microRNA, alternative splicing) mechanisms implicated in mental illness, focusing on a key serotonin-related regulator, the serotonin 1A (5-HT1A) receptor. Functional single-nucleotide polymorphisms and stress-induced DNA methylation of the 5-HT1A promoter converge to differentially alter pre- and postsynaptic 5-HT1A receptor expression associated with major depression and reduced therapeutic response to serotonergic antidepressants. Major depression is also associated with altered levels of splice factors and microRNA, posttranscriptional mechanisms that regulate RNA stability. The human 5-HT1A 3′-untranslated region is alternatively spliced, removing microRNA sites and increasing 5-HT1A expression, which is reduced in major depression and may be genotype-dependent. Thus, the 5-HT1A receptor gene illustrates the convergence of genetic, epigenetic and posttranscriptional mechanisms in gene expression, neurodevelopment and neuroplasticity, and major depression. Understanding gene regulatory mechanisms could enhance the detection, categorization and personalized treatment of major depression.
重度抑郁症和焦虑症普遍存在，且涉及 5-羟色胺的慢性失调，但人们对其仍知之甚少。在这里，我们回顾了与精神疾病相关的新型转录（遗传、表观遗传）和转录后（microRNA、可变剪接）机制，重点关注关键的 5-羟色胺相关调节剂——5-羟色胺 1A（5-HT1A）受体。功能性单核苷酸多态性和应激诱导的 5-HT1A 启动子 DNA 甲基化，导致与重度抑郁症相关的前突触和后突触 5-HT1A 受体表达的差异改变，以及对 5-羟色胺能抗抑郁药治疗反应的降低。重度抑郁症还与剪接因子和 microRNA 水平的改变有关，这些是调节 RNA 稳定性的转录后机制。人类 5-HT1A 3′-非翻译区发生可变剪接，去除 microRNA 位点并增加 5-HT1A 的表达，在重度抑郁症中表达降低，且可能依赖于基因型。因此，5-HT1A 受体基因说明了遗传、表观遗传和转录后机制在基因表达、神经发育和神经可塑性以及重度抑郁症中的汇聚。了解基因调控机制可以提高对重度抑郁症的检测、分类和个体化治疗。
