Schizophrenia is highly heritable and aggregating in families, but genetics alone does not exclusively explain the pathogenesis. Many risk factors, including childhood trauma, viral infections, migration, and the use of cannabis, are associated with schizophrenia. Adolescence seems to be the critical period where symptoms of the disease manifest. This work focuses on studying an epigenetic regulatory mechanism (the role of DNA methylation) and its interaction with mRNA expression during development, with a particular emphasis on adolescence. The presumptions regarding the role of aberrant neurodevelopment in schizophrenia were tested in the Methyl-Azoxy-Methanol (MAM) animal model. MAM treatment induces neurodevelopmental disruptions and behavioral deficits in off-springs of the treated animals reminiscent of those observed in schizophrenia and is thus considered a promising model for studying this pathology. On a gestational day-17, adult pregnant rats were treated with the antimitotic agent MAM. Experimental animals were divided into groups and subgroups according to substance treatment (MAM and vehicle agent [Sham]) and age of analysis (pre-adolescent and post-adolescent). Methylation and mRNA expression analysis of four candidate genes, which are often implicated in schizophrenia, with special emphasis on the Dopamine hypothesis i.e., Dopamine receptor D₂ (Drd2), and the “co-factors” Disrupted in schizophrenia 1 (DISC1), Synaptophysin (Syp), and Dystrobrevin-binding protein 1 (Dtnbp1), was performed in the Gyrus cingulum (CING) and prefrontal cortex (PFC). Data were analyzed to observe the effect of substance treatment between groups and the impact of adolescence within-group. We found reduced pre-adolescent expression levels of Drd2 in both brain areas under the application of MAM. The “co-factor genes” did not show high deviations in mRNA expression levels but high alterations of methylation rates under the application of MAM (up to ~20%), which diminished in the further time course, reaching a comparable level like in Sham control animals after adolescence. The pre-adolescent reduction in DRD2 expression might be interpreted as downregulation of the receptor due to hyperdopaminergic signaling from the ventral tegmental area (VTA), eventually even to both investigated brain regions. The notable alterations of methylation rates in the three analyzed co-factor genes might be interpreted as attempt to compensate for the altered dopaminergic neurotransmission.

精神分裂症具有高度遗传性和家族聚集性，但仅靠遗传学并不能完全解释其发病机制。许多危险因素，包括童年创伤、病毒感染、迁移和吸食大麻，都与精神分裂症有关。青春期似乎是疾病症状显现的关键时期。这项工作的重点是研究表观遗传调控机制（DNA 甲基化的作用）及其在发育过程中与 mRNA 表达的相互作用，特别强调青春期。在甲基偶氮甲醇 (MAM) 动物模型中测试了关于神经发育异常在精神分裂症中的作用的假设。MAM 治疗会导致受治疗动物后代的神经发育中断和行为缺陷，让人联想到在精神分裂症中观察到的那些，因此被认为是研究这种病理学的有前途的模型。在妊娠第 17 天，用抗有丝分裂剂 MAM 治疗成年怀孕大鼠。根据物质处理（MAM 和载体剂 [Sham]）和分析年龄（青春期前和青春期后）将实验动物分为组和亚组。四个候选基因的甲基化和 mRNA 表达分析，通常与精神分裂症有关，特别强调多巴胺假说，即多巴胺受体 D 根据物质处理（MAM 和载体剂 [Sham]）和分析年龄（青春期前和青春期后）将实验动物分为组和亚组。四个候选基因的甲基化和 mRNA 表达分析，通常与精神分裂症有关，特别强调多巴胺假说，即多巴胺受体 D 根据物质处理（MAM 和载体剂 [Sham]）和分析年龄（青春期前和青春期后）将实验动物分为组和亚组。四个候选基因的甲基化和 mRNA 表达分析，通常与精神分裂症有关，特别强调多巴胺假说，即多巴胺受体 D₂ ( Drd2 ) 和精神分裂症 1 ( DISC1 )、突触素 ( Syp )和 Dystrobrevin 结合蛋白 1 ( Dtnbp1 )中被破坏的“辅助因子” ，在扣带回 (CING) 和前额叶皮层 (PFC) 中进行. 分析数据以观察组间物质治疗的效果和组内青春期的影响。我们发现Drd2的青春期前表达水平降低在 MAM 的应用下，两个大脑区域。“辅助因子基因”在 mRNA 表达水平上没有表现出高偏差，但在 MAM 的应用下甲基化率发生了高变化（高达 ~20%），随着时间的推移逐渐减少，达到与 Sham 相当的水平控制青春期后的动物。DRD2 表达在青春期前的减少可能被解释为由于来自腹侧被盖区 (VTA) 的高多巴胺能信号传导导致的受体下调，最终甚至到达两个被研究的大脑区域。三个分析的辅因子基因中甲基化率的显着变化可能被解释为试图补偿改变的多巴胺能神经传递。