Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen Medical Centre, Geert Grooteplein 21, 6525 EZ Nijmegen, The Netherlands.
Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
Neurosci Biobehav Rev. 2014 Jun;43:35-47. doi: 10.1016/j.neubiorev.2014.03.012. Epub 2014 Apr 3.
Serotonin (5-HT) and brain-derived neurotrophin factor (BDNF) are known to modulate behavioral responses to stress and to mediate the therapeutic efficacy of antidepressant agents through neuroplastic and epigenetic mechanisms. While the two systems interact at several levels, this scenario is complicated by a number of variants including brain region specificity, 5-HT receptor selectivity and timing. Based on recent insights obtained using 5-HT transporter (5-HTT) knockout rats we here set-out and discuss the crucial role of neurodevelopmental mechanisms and the contribution of transcription factors and epigenetic modifications to this interaction and its variants. 5-HTT knockout in rats, as well as the low activity short allelic variant of the serotonin transporter human polymorphism, consistently show reduced BDNF mRNA and protein levels in the hippocampus and in the prefrontal cortex. This starts during the second postnatal week, is preceded by DNA hypermethylation during the first postnatal week, and it is developmentally paralleled by reduced expression of key transcription factors. The reduced BDNF levels, in turn, affect 5-HT1A receptor-mediated intracellular signaling and thereby the serotonergic phenotype of the neurons. We propose that such a negative spiral of modifications may affect brain development and reduce its resiliency to environmental challenges during critical time windows, which may lead to phenotypic alterations that persist for the entire life. The characterization of 5-HT-BDNF interactions will eventually increase the understanding of mental illness etiology and, possibly, lead to the identification of novel molecular targets for drug development.
血清素（5-HT）和脑源性神经营养因子（BDNF）已知可以调节对压力的行为反应，并通过神经可塑性和表观遗传机制来介导抗抑郁药的治疗效果。虽然这两个系统在多个层面上相互作用，但这种情况因包括脑区特异性、5-HT 受体选择性和时间等多种变体而变得复杂。基于最近使用 5-羟色胺转运体（5-HTT）敲除大鼠获得的新见解，我们在此提出并讨论了神经发育机制的关键作用，以及转录因子和表观遗传修饰对这种相互作用及其变体的贡献。大鼠的 5-HTT 敲除以及人类 5-羟色胺转运体多态性的低活性短等位基因变体，一致显示海马体和前额叶皮层中的 BDNF mRNA 和蛋白水平降低。这种情况始于出生后的第二周，之前是出生后的第一周的 DNA 超甲基化，并且与关键转录因子的表达减少在发育上平行。反过来，减少的 BDNF 水平会影响 5-HT1A 受体介导的细胞内信号转导，从而影响神经元的 5-羟色胺能表型。我们提出，这种修饰的负反馈循环可能会影响大脑发育，并在关键时间窗口降低其对环境挑战的适应能力，从而导致持续一生的表型改变。5-HT-BDNF 相互作用的特征最终将增加对精神疾病病因的理解，并可能导致识别用于药物开发的新分子靶标。
