Department of Psychiatry and Neuroscience, Division of Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-Ku, Kasumi 1-2-3, Hiroshima City, Hiroshima, Japan.
Department of Psychology, School of Faculty of Health and Wellness Sciences, Hiroshima International University, Kure, Japan.
Psychopharmacology (Berl). 2024 Nov;241(11):2363-2374. doi: 10.1007/s00213-024-06640-7. Epub 2024 Jun 28.
Since the precise mechanisms of posttraumatic stress disorder (PTSD) remain unknown, effective treatment interventions have not yet been established. Impaired extinction of fear memory (EFM) is one of the core symptoms of PTSD and is associated with stress-induced epigenetic change in gene expression.
In this study, we examined whether the involvement of histone H3 lysine 9 dimethylation (H3K9me2) in EFM is mediated through brain-derived neurotrophic factor (BDNF) expression in the hippocampus, and whether BIX01294, a selective G9a and GLP histone methyltransferase inhibitor, could be treatment for impaired EFM in an animal model of PTSD.
The single prolonged stress (SPS) paradigm was used to model PTSD. We measured BDNF mRNA levels by RT-PCR, and H3K9me2 levels in the BDNF gene promoters by chromatin immunoprecipitation-qPCR. After undergoing contextual fear conditioning and hippocampal injection of BIX01294, male rats were subjected to extinction training and extinction testing and their freezing times and BDNF mRNA levels were measured.
Compared to sham rats, SPS rats showed decreased BDNF mRNA levels 2 h after extinction training, no significant changes in levels of global H3K9me2 prior to extinction training, and increased levels of H3K9me2 in BDNF gene promoter IV, but not in BDNF gene promoter I. Administration of BIX01294 ameliorated the decrease in BDNF mRNA levels 2 h after extinction training and subsequently alleviated impaired EFM in extinction tests in SPS rats.
We conclude that reduced hippocampal levels of BDNF mRNA due to increase in H3K9me2 levels may play a role in PTSD-associated EFM impairment, and BIX01294 could be a PTSD treatment option.
由于创伤后应激障碍（PTSD）的确切机制尚不清楚，因此尚未建立有效的治疗干预措施。恐惧记忆的消除受损（EFM）是 PTSD 的核心症状之一，与应激诱导的基因表达表观遗传变化有关。
在这项研究中，我们研究了海马体中组蛋白 H3 赖氨酸 9 二甲基化（H3K9me2）是否通过脑源性神经营养因子（BDNF）的表达参与 EFM，以及 BIX01294（一种选择性 G9a 和 GLP 组蛋白甲基转移酶抑制剂）是否可以治疗 PTSD 动物模型中的 EFM 受损。
使用单一延长应激（SPS）范式来模拟 PTSD。我们通过 RT-PCR 测量 BDNF mRNA 水平，通过染色质免疫沉淀-qPCR 测量 BDNF 基因启动子中的 H3K9me2 水平。雄性大鼠接受情境恐惧条件反射和海马体注射 BIX01294 后，进行消退训练和消退测试，并测量其冻结时间和 BDNF mRNA 水平。
与假手术大鼠相比，SPS 大鼠在消退训练后 2 小时 BDNF mRNA 水平降低，消退训练前 H3K9me2 总水平无明显变化，BDNF 基因启动子 IV 中的 H3K9me2 水平升高，但基因启动子 I 中的 H3K9me2 水平没有升高。BIX01294 的给药改善了消退训练后 2 小时 BDNF mRNA 水平的降低，并随后缓解了 SPS 大鼠在消退测试中 EFM 受损。
我们的结论是，由于 H3K9me2 水平升高导致海马体 BDNF mRNA 水平降低可能在 PTSD 相关 EFM 受损中起作用，BIX01294 可能是 PTSD 的治疗选择。
