Brain-derived neurotrophic factor epigenetic modifications associated with schizophrenia-like phenotype induced by prenatal stress in mice.
Brain-derived neurotrophic factor epigenetic modifications associated with schizophrenia-like phenotype induced by prenatal stress in mice.
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DOI：
10.1016/j.biopsych.2014.08.012
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发表时间：
2015-03-15
影响因子：
10.6
通讯作者：
Guidotti A
中科院分区：
文献类型：
--
作者：
Dong E;Dzitoyeva SG;Matrisciano F;Tueting P;Grayson DR;Guidotti A
产前压力被认为是包括精神分裂症（SZ）在内的几种神经发育障碍的危险因素。一种涉及妊娠小鼠束缚应激的动物模型表明，产前应激（PRS）诱导可能与SZ有关的特定GABA能和谷氨酸能基因（包括脑源性神经营养因子（BDNF）基因）的表观遗传变化。以孕鼠成年子代为研究对象，探讨了PRS对行为和关键染色质重塑因子表达的长期影响，这些因子包括DNA甲基转移酶1（DNMT 1）、10 - 11易位羟化酶（THEX）、甲基CpG结合蛋白2（MeCP 2）、组蛋白脱乙酰酶（HDAC）、组蛋白甲基转移酶（MITH 1）、组蛋白甲基转移酶（MITH 2）、组蛋白甲基转移酶（M（MLL 1、SETD 1、G9 A和EZH 1）和去甲基酶（LSD 1）。我们还检测了BDNF的表达。成年PRS后代表现出行为异常，提示SZ和类似于SZ死后大脑的分子变化：FC和HP中的DNMT 1和TET 1显著增加，但小脑中没有，HDAC，组蛋白甲基转移酶/脱甲基酶或MeCP 2没有变化，FC和HP中测量的BDNF变体显著减少。相应的BDNF转录水平的降低被BDNF基因调控区5-甲基胞嘧啶和5-羟甲基胞嘧啶水平的富集所抵消。此外，BDNF转录本（IV和IX）的表达与PRS和非应激小鼠的社交方式呈正相关。由于精神病患者和PRS小鼠表现出相似的表观遗传特征，PRS后代可能是了解SZ患者中观察到的行为和分子表观遗传变化的合适模型。
Prenatal stress is considered a risk factor for several neurodevelopmental disorders including schizophrenia (SZ). An animal model involving restraint stress of pregnant mice suggests that prenatal stress (PRS) induces epigenetic changes in specific GABAergic and glutamatergic genes likely to be implicated in SZ including the gene for brain derived neurotrophic factor (BDNF). Studying adult offspring of pregnant mice subjected to PRS, we explored the long-term effect of PRS on behavior and on the expression of key chromatin remodeling factors including DNA methyltransferase 1 (DNMT1), ten-eleven translocation hydroxylases (TETs), methyl CpG binding protein 2 (MeCP2), histone deacetylases (HDACs), histone methyltransferases (MLL1, SETD1, G9A and EZH1) and demethylase (LSD1) in the frontal cortex (FC) and hippocampus (HP). We also measured the expression of BDNF. Adult PRS offspring demonstrate behavioral abnormalities suggestive of SZ and molecular changes similar to SZ postmortem brain: a significant increase in DNMT1 and TET1 in the FC and HP but not in cerebellum, no changes in HDACs, histone methytransferases/demethylases or MeCP2, and a significant decrease in BDNF variants measured in the FC and HP. The decrease of the corresponding BDNF transcript level was paralleled by an enrichment of 5-methylcytosine and 5-hydroxylmethylcytosine levels at Bdnf gene regulatory regions. In addition, the expression of BDNF transcripts (IV and IX) was positively correlated with social approach in both PRS and non-stressed mice. Since patients with psychosis and PRS mice show similar epigenetic signature, PRS offspring may be a suitable model for understanding the behavioral and molecular epigenetic changes observed in SZ patients.
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