Discovery of a cerebellar-specific BAF chromatin remodeler that is necessary for social inhibition: molecular and circuit mechanisms

发现社交抑制所必需的小脑特异性 BAF 染色质重塑剂：分子和电路机制

• 批准号: 10619389
• 负责人: Wendy Christine Wenderski
• 金额: $ 8.27万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-09 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619389
• 关键词: ACTL6B gene; ATAC-seq; Action Potentials; Affect; Agonist; Alleles; Anatomy; Animal Model; Animals; BRAIN initiative; Behavior; Behavior Control; Biological Assay; Biology; Brain; Child; Chromatin; Chromatin Remodeling Factor; Collaborations; Complex; DNA Sequence Alteration; Data; Development; Disease; Doctor of Philosophy; ERG gene; Epigenetic Process; Etiology; Exhibits; Family; Future; Gene Activation; Gene Silencing; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Heritability; Histone Acetylation; Human; Impairment; Inherited; Investigation; Knockout Mice; Laboratories; Learning; Link; Malignant Neoplasms; Memory; Mentors; Mission; Modeling; Molecular; Mus; Mutate; Mutation; NCOR1 gene; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Neurosciences; Nuclear Extract; Nucleosomes; Pathway interactions; Phase; Phenotype; Population Control; Postdoctoral Fellow; Repression; Research; Research Assistant; Research Project Grants; Research Support; Rest; Risk; Role; Running; Seminal; Serotonin Receptor 5-HT1B; Site; Social Behavior; Social Responsibility; Synaptic plasticity; System; Testing; Tissues; Training; Transcription Factor AP-1; Treatment Efficacy; United States National Institutes of Health; Universities; Work; autism spectrum disorder; autistic behaviour; behavior influence; brain circuitry; cell type; chromatin remodeling; derepression; empowerment; experimental study; genetic regulatory protein; histone modification; impression; insight; mouse model; mutant; neural; neural circuit; neurodevelopment; neuron loss; neuronal circuitry; new therapeutic target; post-doctoral training; response; skills; social; social communication impairment; tool; transcription factor; transcriptome sequencing

Project Summary Autism spectrum disorder (ASD) is a highly prevalent group of neurodevelopmental disorders whose treatment efficacy is limited by poor understanding of its causal molecular mechanisms. Identifying disease mechanisms in ASD involves overcoming several challenges. First, it is difficult to demonstrate causality for a given mutation, since many mutations increase risk but do not always produce ASD. Second, it is challenging to identify animal models with autism-related phenotypes that are robust across multiple genetic backgrounds. Third, limited understanding of the neuronal subtypes and circuits responsible for behavior is a barrier to studying molecular mechanisms in a disease-relevant cellular context. The proposed research meets all three of these challenges. In the F99 phase, human families with a highly penetrant form of recessive autism caused by mutations in ACTL6B, a neuronal-specific subunit of the BAF chromatin remodeling complex, were identified. Actl6b-/- mice were tested as a model for ACTL6B mutant ASD and found to exhibit autism-related behaviors on two genetic backgrounds and similar brain anatomy to the affected humans. Transcriptional analysis of Actl6b-/- cortical cultures indicated that neural activity-induced genes were de-repressed in the absence of Actl6b, even when action potentials were blocked. The elevated expression of early response genes, including AP1 transcription factors (e.g., Fos, Junb), in Actl6b-/- neurons was associated with increased chromatin accessibility at AP1 sites and activity-related transcriptional changes in late-response genes, implicating abnormal early response gene activation as a potential disease mechanism. The genomic localization of the BAF complex, AP1 transcription factors, and the NCoR complex, which interacted with BAF in cortical tissue, will be studied in wildtype and Actl6b-/- neurons to learn if altered targeting of these complexes may contribute to disease-related transcriptional changes. To gain insight into the affected neuronal circuitry, a serotonin receptor 1b (5HT1b) agonist that was shown to rescue social behavior in the 16p11 autism mouse model (PMID: 30089910) was tested and found to rescue social impairments in Actl6b-/- mice. Serotonergic neuron-specific deletion of Arid1b, the most frequently mutated BAF subunit in autism, caused social impairments in mice that could likewise be rescued with the 5HT1b agonist, indicating that BAF function in serotonergic neurons is critical for social behavior. These studies have inspired the postdoctoral (K00) research direction: to interrogate autism-related molecular mechanisms within neuronal populations that control behavior. The postdoctoral training in systems neuroscience will buoy future studies linking the functions of chromatin regulatory proteins directly to behavior. This research supports the missions of the NIH Blueprint and BRAIN Initiative by providing new tools for autism research and revealing molecular and circuit mechanisms that influence behavior.

项目概要 自闭症谱系障碍 (ASD) 是一组非常普遍的神经发育障碍，其治疗方法 由于对其因果分子机制了解不足，其功效受到限制。确定疾病机制 自闭症谱系障碍（ASD）涉及克服一些挑战。首先，很难证明给定的因果关系 突变，因为许多突变会增加风险，但并不总是产生 ASD。其次，具有挑战性 识别具有自闭症相关表型的动物模型，这些模型在多种遗传背景下都具有稳健性。 第三，对负责行为的神经元亚型和回路的了解有限是实现这一目标的障碍。 研究疾病相关细胞背景下的分子机制。拟议的研究满足所有三个 这些挑战。在F99阶段，患有高度渗透性隐性自闭症的人类家庭引起了 ACTL6B（BAF 染色质重塑复合物的神经元特异性亚基）的突变 确定。 Actl6b-/- 小鼠作为 ACTL6B 突变 ASD 模型进行测试，发现表现出与自闭症相关的 两种遗传背景的行为以及与受影响人类相似的大脑解剖结构。转录的 Actl6b-/- 皮质培养物的分析表明，神经活动诱导的基因在 Actl6b 缺失，即使动作电位被阻断。早期反应表达升高 Actl6b-/- 神经元中的基因，包括 AP1 转录因子（例如 Fos、Junb）与增加 AP1 位点的染色质可及性和晚期反应基因中与活性相关的转录变化， 暗示异常的早期反应基因激活是一种潜在的疾病机制。基因组 BAF 复合体、AP1 转录因子和 NCoR 复合体（与 BAF 相互作用）的定位 在皮质组织中，将在野生型和 Actl6b-/- 神经元中进行研究，以了解这些神经元的靶向是否改变 复合物可能导致与疾病相关的转录变化。为了深入了解受影响的神经元 电路，一种血清素受体 1b (5HT1b) 激动剂，被证明可以挽救 16p11 的社交行为 自闭症小鼠模型（PMID：30089910）经过测试，发现可以挽救 Actl6b-/- 小鼠的社交障碍。 Arid1b（自闭症中最常见突变的 BAF 亚基）的血清素能神经元特异性缺失，导致 小鼠的社交障碍同样可以用 5HT1b 激动剂来挽救，这表明 BAF 功能 血清素能神经元对社会行为至关重要。这些研究启发了博士后（K00） 研究方向：探究神经元群体内与自闭症相关的分子机制 控制行为。系统神经科学的博士后培训将推动未来的研究 染色质调节蛋白的功能直接影响行为。这项研究支持了该组织的使命 NIH Blueprint 和 BRAIN Initiative 为自闭症研究提供新工具并揭示分子和 影响行为的电路机制。