Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, 37077 Goettingen, Germany.
Research Group for Genome Dynamics in Brain Diseases, 37077 Goettingen, Germany.
Proc Natl Acad Sci U S A. 2017 Jun 6;114(23):E4686-E4694. doi: 10.1073/pnas.1613842114. Epub 2017 May 22.
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 () expression that is linked to altered DNA methylation. 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 expression in blood. Moreover, 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.
精神分裂症是一种严重的疾病，它是在遗传易感性和环境风险因素（如早期生活应激，ELS）的背景下产生的。在这项研究中，我们表明，ELS 在小鼠中诱导的类似精神分裂症的表型与组蛋白去乙酰化酶 1（HDAC1）表达的广泛增加相关，这种增加与 DNA 甲基化的改变有关。HDAC1 在中前额叶皮层神经元中的过表达，但不在背侧或腹侧海马体中，模拟了 ELS 诱导的类似精神分裂症的表型。当在疾病表型出现后应用时，全身性给予 HDAC 抑制剂可挽救 ELS 的有害作用。除了海马体和前额叶皮层外，经历 ELS 的小鼠在血液中表现出增加的 HDAC1 表达。此外，与没有 ELS 经历的患者相比，经历过 ELS 的精神分裂症患者的血液样本中的水平升高。我们的数据表明，HDAC1 抑制应该被认为是治疗精神分裂症的一种治疗方法。
