The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
Neuropsychopharmacology. 2013 Jan;38(1):138-66. doi: 10.1038/npp.2012.125. Epub 2012 Sep 5.
Major psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BP) with psychosis (BP+) express a complex symptomatology characterized by positive symptoms, negative symptoms, and cognitive impairment. Postmortem studies of human SZ and BP+ brains show considerable alterations in the transcriptome of a variety of cortical structures, including multiple mRNAs that are downregulated in both inhibitory GABAergic and excitatory pyramidal neurons compared with non-psychiatric subjects (NPS). Several reports show increased expression of DNA methyltransferases in telencephalic GABAergic neurons. Accumulating evidence suggests a critical role for altered DNA methylation processes in the pathogenesis of SZ and related psychiatric disorders. The establishment and maintenance of CpG site methylation is essential during central nervous system differentiation and this methylation has been implicated in synaptic plasticity, learning, and memory. Atypical hypermethylation of candidate gene promoters expressed in GABAergic neurons is associated with transcriptional downregulation of the corresponding mRNAs, including glutamic acid decarboxylase 67 (GAD67) and reelin (RELN). Recent reports indicate that the methylation status of promoter proximal CpG dinucleotides is in a dynamic balance between DNA methylation and DNA hydroxymethylation. Hydroxymethylation and subsequent DNA demethylation is more complex and involves additional proteins downstream of 5-hydroxymethylcytosine, including members of the base excision repair (BER) pathway. Recent advances in our understanding of altered CpG methylation, hydroxymethylation, and active DNA demethylation provide a framework for the identification of new targets, which may be exploited for the pharmacological intervention of the psychosis associated with SZ and possibly BP+.
主要的精神疾病，如精神分裂症（SZ）和伴有精神病性症状的双相情感障碍（BP+），表现出一种复杂的症状学特征，包括阳性症状、阴性症状和认知障碍。SZ 和 BP+大脑的人体死后研究表明，各种皮质结构的转录组发生了相当大的改变，包括与非精神病个体（NPS）相比，抑制性 GABA 能和兴奋性锥体神经元中的多种 mRNA 下调。有几项报道表明，在端脑 GABA 能神经元中 DNA 甲基转移酶的表达增加。越来越多的证据表明，DNA 甲基化过程的改变在 SZ 和相关精神疾病的发病机制中起着关键作用。在中枢神经系统分化过程中，CpG 位点甲基化的建立和维持是必不可少的，这种甲基化与突触可塑性、学习和记忆有关。在 GABA 能神经元中表达的候选基因启动子的非典型过度甲基化与相应 mRNA 的转录下调有关，包括谷氨酸脱羧酶 67（GAD67）和 reelin（RELN）。最近的报告表明，启动子近端 CpG 二核苷酸的甲基化状态在 DNA 甲基化和 DNA 羟甲基化之间处于动态平衡。羟甲基化和随后的 DNA 去甲基化更为复杂，涉及 5-羟甲基胞嘧啶下游的额外蛋白质，包括碱基切除修复（BER）途径的成员。我们对改变的 CpG 甲基化、羟甲基化和活性 DNA 去甲基化的理解的最新进展为鉴定新的靶点提供了一个框架，这些靶点可能被用于药理学干预与 SZ 相关的精神病，可能还有 BP+。
