Department of Internal Medicine, Division of Clinical Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield, UK.
J Psychopharmacol. 2022 Feb;36(2):238-244. doi: 10.1177/02698811211069109. Epub 2022 Feb 1.
N-methyl-d-aspartate receptor (NMDAR) dysfunction is implicated in schizophrenia, and NMDAR antagonists, such as phencyclidine (PCP), can induce behaviours that mimic aspects of the disorder.
We investigated DNA methylation of and promoter region and NR1 and NR2 protein expression in the prefrontal cortex (PFC) and hippocampus of adult female Lister-hooded rats following subchronic PCP (scPCP) administration. We also determined whether any alterations were tissue-specific.
Rats were divided into two groups that received vehicle (0.9% saline) or 2 mg/kg PCP twice a day for 7 days (n = 10 per group). After behavioural testing (novel object recognition), to confirm a cognitive deficit, brains were dissected and NMDAR subunit DNA methylation and protein expression were analysed by pyrosequencing and ELISA. methylation was determined as a measure of global methylation. Data were analysed using Student's -test and Pearson correlation.
The scPCP administration led to and hypermethylation and reduction in NR1 protein in both PFC and hippocampus. No significant differences were observed in or methylation and NR2 protein.
The scPCP treatment resulted in increased DNA methylation at promoter sites of and NMDAR subunits in two brain areas implicated in schizophrenia, independent of any global change in DNA methylation, and are similar to our observations in a neurodevelopmental animal model of schizophrenia - social isolation rearing post-weaning. Moreover, these alterations may contribute to the changes in protein expression for NMDAR subunits demonstrating the potential importance of epigenetic mechanisms in schizophrenia.
N-甲基-D-天冬氨酸受体（NMDAR）功能障碍与精神分裂症有关，NMDAR 拮抗剂，如苯环己哌啶（PCP），可诱导模仿该疾病某些方面的行为。
我们研究了亚慢性 PCP（scPCP）给药后成年雌性 Lister-hooded 大鼠前额叶皮层（PFC）和海马中 和 启动子区域的 DNA 甲基化和 NR1 和 NR2 蛋白表达情况，并确定了这些变化是否具有组织特异性。
将大鼠分为两组，一组接受 vehicle（0.9%生理盐水），另一组接受 2mg/kg PCP，每天两次，共 7 天（每组 10 只）。在行为测试（新物体识别）后，为了确认认知缺陷，将大脑解剖并通过焦磷酸测序和 ELISA 分析 NMDAR 亚基 DNA 甲基化和蛋白表达。 甲基化被确定为整体甲基化的衡量标准。使用 Student's -test 和 Pearson 相关分析数据。
scPCP 给药导致 PFC 和海马中 和 启动子区域的过度甲基化和 NR1 蛋白减少。 或 甲基化和 NR2 蛋白无明显差异。
scPCP 处理导致两个与精神分裂症有关的脑区 NMDAR 亚基的启动子区域的 DNA 甲基化增加，与任何整体 DNA 甲基化变化无关，与我们在精神分裂症的神经发育动物模型 - 社交隔离饲养后(post-weaning)的观察结果相似。此外，这些变化可能导致 NMDAR 亚基蛋白表达的变化，表明表观遗传机制在精神分裂症中的潜在重要性。
