Center of Neuropharmacology, Department of Pharmacological Sciences, Universita' degli Studi di Milano, Milan, Italy.
Neurobiol Dis. 2010 Mar;37(3):747-55. doi: 10.1016/j.nbd.2009.12.014. Epub 2009 Dec 23.
In order to identify the molecular mechanisms that may contribute to the enhanced susceptibility to depression under serotonin transporter (SERT) dysfunction, we analyzed the expression of brain-derived neurotrophic factor (BDNF), a key player in neuronal plasticity, which is implicated in the etiology and treatment of depression. We found that BDNF levels were significantly reduced in the hippocampus and prefrontal cortex of SERT knockout rats, through transcriptional changes that affect different neurotrophin isoforms. The reduction of BDNF gene expression observed in prefrontal cortex is due, at least in part, to epigenetic changes that affect the promoter regions of exons IV and VI. Moreover, BDNF gene expression is also significantly reduced in leukocytes from healthy subjects carrying the S allele of the 5-HTTLPR, suggesting that the changes observed in SERT mutant rats may also be present in humans and may confer enhanced vulnerability to mood disorders.
为了确定可能导致血清素转运体 (SERT) 功能障碍下抑郁易感性增加的分子机制，我们分析了脑源性神经营养因子 (BDNF) 的表达，BDNF 是神经元可塑性的关键因子，与抑郁的病因和治疗有关。我们发现，通过影响不同神经营养因子同工型的转录变化，SERT 敲除大鼠的海马体和前额叶皮层中的 BDNF 水平显著降低。在观察到的前额叶皮层中 BDNF 基因表达的减少，至少部分归因于影响外显子 IV 和 VI 启动子区域的表观遗传变化。此外，携带 5-HTTLPR 的 S 等位基因的健康受试者的白细胞中的 BDNF 基因表达也显著降低，这表明在 SERT 突变大鼠中观察到的变化也可能存在于人类中，并可能导致对情绪障碍的易感性增强。
