Remodeling Neuronal Chromatin in Mouse Models for Depression

重塑抑郁症小鼠模型中的神经元染色质

基本信息

项目摘要

DESCRIPTION (provided by applicant): Currently available antidepressant drugs typically modulate serotonergic, noradrenergic or dopaminergic neurotransmission and take 6-8 weeks to exert their effects. In addition, for each drug, up to 50-60% of patients show inadequate responses in treatment trials. Therefore, it will be important to explore novel antidepressant treatment strategies in pre-clinical studies. It has been suggested that chromatin remodeling mechanisms, including histone modification changes, play an important role for the neurobiology of depressive disorders. The foundations of this hypothesis are built on two observations in the pre-clinical model, (i) commonly used treatments, including antidepressant drugs and electroconvulsive seizures, induce dynamic changes in histone acetylation, and (ii) drugs that inhibit histone deacetylases (HDACs) exhibit antidepressant-like effects, or enhance the therapeutic effect of a conventional antidepressant such as fluoxetine. Based on these findings, it is assumed that drug induced hyperacetylation of histones and the resulting antidepressant effect is linked to "a loosening of chromatin structures and transcriptional activation". However, little is known about the neurological and behavioral phenotypes resulting from experimental manipulation of other histone modifications and histone modifying enzymes, particularly those defined by a genome-wide enrichment pattern that is highly divergent as compared to acetylation. To address these issues, we generated mice with a sustained increase in neuronal expression of Setdb1, encoding a developmentally regulated histone H3-lysine 9 specific histone methyltransferase associated with Sin3a-deacetylase, KAP-1 and NuRD transcriptional repressor complexes. Contrary to our original hypothesis, our preliminary data show that a sustained increase in Setdb1 levels in the forebrain is associated with antidepressant-like changes in behavioral despair and learned helplessness paradigms. Unexpectedly, Setdb1 occupancies in the genome were highly restricted overall, while enriched at several loci encoding glutamate receptor genes. This resulted in decreased levels of the NMDA receptor subunit Grin2b (NR2B) in prefrontal cortex and hippocampus. This finding is interesting because the non-specific NMDA receptor antagonist, ketamine, and the NR2B selective antagonist, CP101,606 elicit rapid antidepressant action in depressed subjects, including a subset of cases who had failed to respond to conventional treatments . The focus of this preclinical proposal is to explore the link between antidepressant-like phenotypes of Setdb1 transgenic mice, and the transcriptional regulation of NMDA receptor subunit Grin2b, and other gene expression changes, and to uncover novel treatment strategies for affective disorders. Our experiments utilize a comprehensive toolbox of in vivo and ex vivo approaches, including (a) multiple lines of genetically engineered mice to target the regulation of histone (H3-lysine 9) methylation in neuronal chromatin, (b) procedures to isolate neuronal chromatin from brain tissue, (c) chromatin immunoprecipitation followed by genome-wide profiling, (d) behavioral assays measuring despair and learned helplessness, anxiety, and learning and memory and (e) functional characterization of NMDA receptors in hippocampus and other brain regions implicated in the neurobiology of depression. This proposal will explore the antidepressant potential of Setdb1-regulated histone methylation, including the potential link to NMDA receptor-mediated signaling, thus offering the perspective of introducing a radically new treatment principle for a major psychiatric disorder.
描述(由申请人提供):目前可用的抗抑郁药物通常调节血清素能、去甲肾上腺素能或多巴胺能神经传递,并需要 6-8 周才能发挥作用。此外,对于每种药物,高达 50-60% 的患者在治疗试验中表现出不充分的反应。因此,在临床前研究中探索新型抗抑郁治疗策略非常重要。有人提出,染色质重塑机制,包括组蛋白修饰变化,在抑郁症的神经生物学中发挥着重要作用。这一假设的基础建立在临床前模型中的两个观察结果之上:(i) 常用的治疗方法,包括抗抑郁药物和电惊厥发作,会引起组蛋白乙酰化的动态变化,以及 (ii) 抑制组蛋白脱乙酰酶 (HDAC) 的药物表现出类似抗抑郁药的作用,或增强传统抗抑郁药(如氟西汀)的治疗效果。基于这些发现,推测药物诱导的组蛋白过度乙酰化以及由此产生的抗抑郁作用与“染色质结构的松弛和转录激活”有关。然而,人们对其他组蛋白修饰和组蛋白修饰酶的实验操作所产生的神经和行为表型知之甚少,特别是那些由与乙酰化相比高度不同的全基因组富集模式定义的那些。为了解决这些问题,我们培育了 Setdb1 神经元表达持续增加的小鼠,Setdb1 编码与 Sin3a-脱乙酰酶、KAP-1 和 NuRD 转录抑制复合物相关的发育调节组蛋白 H3-赖氨酸 9 特异性组蛋白甲基转移酶。与我们最初的假设相反,我们的初步数据表明,前脑中 Setdb1 水平的持续增加与行为绝望和习得性无助范式的抗抑郁样变化有关。出乎意料的是,Setdb1 在基因组中的占据总体上受到高度限制,而在编码谷氨酸受体基因的几个位点上却富集。这导致前额皮质和海马中 NMDA 受体亚基 Grin2b (NR2B) 的水平降低。这一发现很有趣,因为非特异性 NMDA 受体拮抗剂氯胺酮和 NR2B 选择性拮抗剂 CP101,606 在抑郁症受试者中引发快速抗抑郁作用,包括对传统治疗没有反应的一部分病例。该临床前提案的重点是探索 Setdb1 转基因小鼠的抗抑郁样表型与 NMDA 受体亚基 Grin2b 的转录调控以及其他基因表达变化之间的联系,并揭示情感障碍的新治疗策略。我们的实验利用体内和离体方法的综合工具箱,包括(a)多个基因工程小鼠品系,以神经元染色质中组蛋白(H3-赖氨酸9)甲基化的调节为目标,(b)从神经元染色质中分离神经元染色质的程序脑组织,(c) 染色质免疫沉淀,然后进行全基因组分析,(d) 测量绝望和习得性无助、焦虑以及学习和记忆的行为测定,以及 (e) NMDA 的功能表征海马体和其他与抑郁症神经生物学有关的大脑区域的受体。该提案将探索 Setdb1 调节的组蛋白甲基化的抗抑郁潜力,包括与 NMDA 受体介导的信号传导的潜在联系,从而为引入一种针对主要精神疾病的全新治疗原理提供了视角。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Balancing histone methylation activities in psychiatric disorders.
  • DOI:
    10.1016/j.molmed.2011.02.003
  • 发表时间:
    2011-07
  • 期刊:
  • 影响因子:
    13.6
  • 作者:
    Peter CJ;Akbarian S
  • 通讯作者:
    Akbarian S
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Schahram Akbarian其他文献

Schahram Akbarian的其他文献

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{{ truncateString('Schahram Akbarian', 18)}}的其他基金

Cell-lineage specific epigenomic determinants of HIV latency in humanized mouse brain and blood
人源化小鼠大脑和血液中HIV潜伏期的细胞谱系特异性表观基因组决定因素
  • 批准号:
    10747752
  • 财政年份:
    2023
  • 资助金额:
    $ 41.95万
  • 项目类别:
Single Chromatin Fiber Sequencing and Longitudinal Epigenomic Profiling in HIV+ Brain Cells Exposed to Narcotic and Stimulant
暴露于麻醉剂和兴奋剂的 HIV 脑细胞的单染色质纤维测序和纵向表观基因组分析
  • 批准号:
    10457112
  • 财政年份:
    2022
  • 资助金额:
    $ 41.95万
  • 项目类别:
Single Chromatin Fiber Sequencing and Longitudinal Epigenomic Profiling in HIV+ Brain Cells Exposed to Narcotic and Stimulant
暴露于麻醉剂和兴奋剂的 HIV 脑细胞的单染色质纤维测序和纵向表观基因组分析
  • 批准号:
    10595615
  • 财政年份:
    2022
  • 资助金额:
    $ 41.95万
  • 项目类别:
Single nuclei transcriptome profiling in addiction circuitry of the HIV+ brain
HIV大脑成瘾回路的单核转录组分析
  • 批准号:
    10219584
  • 财政年份:
    2021
  • 资助金额:
    $ 41.95万
  • 项目类别:
Modeling HIV Microglia-Associated Infection and Inflammation in a Chimeric Mouse Brain
在嵌合小鼠大脑中模拟 HIV 小胶质细胞相关的感染和炎症
  • 批准号:
    10458060
  • 财政年份:
    2021
  • 资助金额:
    $ 41.95万
  • 项目类别:
Single nuclei transcriptome profiling in addiction circuitry of the HIV+ brain
HIV大脑成瘾回路的单核转录组分析
  • 批准号:
    10783382
  • 财政年份:
    2021
  • 资助金额:
    $ 41.95万
  • 项目类别:
Single nuclei transcriptome profiling in addiction circuitry of the HIV+ brain
HIV大脑成瘾回路的单核转录组分析
  • 批准号:
    10571875
  • 财政年份:
    2021
  • 资助金额:
    $ 41.95万
  • 项目类别:
Single nuclei transcriptome profiling in addiction circuitry of the HIV+ brain
HIV大脑成瘾回路的单核转录组分析
  • 批准号:
    10381603
  • 财政年份:
    2021
  • 资助金额:
    $ 41.95万
  • 项目类别:
Modeling HIV Microglia-Associated Infection and Inflammation in a Chimeric Mouse Brain
在嵌合小鼠大脑中模拟 HIV 小胶质细胞相关的感染和炎症
  • 批准号:
    10632139
  • 财政年份:
    2021
  • 资助金额:
    $ 41.95万
  • 项目类别:
Modeling HIV Microglia-Associated Infection and Inflammation in a Chimeric Mouse Brain
在嵌合小鼠大脑中模拟 HIV 小胶质细胞相关的感染和炎症
  • 批准号:
    10301839
  • 财政年份:
    2021
  • 资助金额:
    $ 41.95万
  • 项目类别:

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