HDAC1 links early life stress to schizophrenia-like phenotypes
HDAC1 links early life stress to schizophrenia-like phenotypes
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DOI：
10.1073/pnas.1613842114
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发表时间：
2017-06-06
影响因子：
11.1
通讯作者：
Fischer, Andre
中科院分区：
文献类型：
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作者：
Bahari-Javan, Sanaz;Varbanov, Hristo;Fischer, Andre
精神分裂症是一种毁灭性疾病，其发病背景是遗传易感性和环境风险因素，如早期生活压力（ELS）。在这项研究中，我们发现els诱导的小鼠精神分裂症样表型与组蛋白去乙酰化酶1 （Hdac1）表达的广泛增加相关，而Hdac1表达与DNA甲基化改变有关。Hdac1在内侧前额皮质神经元中过表达，而在海马背侧或腹侧不表达，模仿ELS诱导的精神分裂症样表型。在疾病表型出现后，全身给药HDAC抑制剂可挽救ELS的有害影响。除海马和前额叶皮层外，ELS小鼠血液中Hdac1表达增加。此外，与没有经历过ELS的患者相比，经历过ELS的精神分裂症患者的血液样本中Hdac1水平升高。我们的数据表明，抑制HDAC1应被视为治疗精神分裂症的一种治疗方法。
Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.