Involvement of dysregulated hippocampal histone H3K9 methylation at the promoter of the BDNF gene in impaired memory extinction.

IF 3.5 3区 医学 Q2 NEUROSCIENCES
Psychopharmacology Pub Date : 2024-11-01 Epub Date: 2024-06-28 DOI:10.1007/s00213-024-06640-7
Kenichi Oga, Manabu Fuchikami, Hironori Kobayashi, Tatsuhiro Miyagi, Sho Fujita, Satoshi Fujita, Satoshi Okada, Shigeru Morinobu
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引用次数: 0

Abstract

Rationale: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Abstract Image

BDNF基因启动子上失调的海马组蛋白H3K9甲基化参与了记忆消退受损的过程
理由:由于创伤后应激障碍(PTSD)的确切机制尚不清楚,有效的治疗干预措施尚未确立。恐惧记忆消退(EFM)受损是创伤后应激障碍的核心症状之一,与应激诱导的基因表达表观遗传变化有关:在这项研究中,我们考察了组蛋白H3赖氨酸9二甲基化(H3K9me2)在EFM中的参与是否通过脑源性神经营养因子(BDNF)在海马中的表达来介导,以及选择性G9a和GLP组蛋白甲基转移酶抑制剂BIX01294是否可以治疗PTSD动物模型中受损的EFM:方法:采用单次长时间应激(SPS)范式来模拟创伤后应激障碍。我们通过RT-PCR检测了BDNF mRNA水平,并通过染色质免疫沉淀-qPCR检测了BDNF基因启动子中的H3K9me2水平。在对雄性大鼠进行情境恐惧条件反射和海马注射BIX01294后,对其进行绝迹训练和绝迹测试,并测定其冻结时间和BDNF mRNA水平:与假大鼠相比,SPS大鼠在绝迹训练2小时后BDNF mRNA水平下降,绝迹训练前全局H3K9me2水平无显著变化,BDNF基因启动子IV中的H3K9me2水平升高,而BDNF基因启动子I中的H3K9me2水平未升高:我们得出结论:H3K9me2水平升高导致海马BDNF mRNA水平降低,这可能是创伤后应激障碍相关EFM损伤的原因之一,BIX01294可能是治疗创伤后应激障碍的一种选择。
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来源期刊
Psychopharmacology
Psychopharmacology 医学-精神病学
CiteScore
7.10
自引率
5.90%
发文量
257
审稿时长
2-4 weeks
期刊介绍: Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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