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.

项目摘要 自闭症谱系障碍(ASD)是一组高度流行的神经发育障碍，其治疗 疗效受到对其致病分子机制认识不足的限制。确定致病机制 在ASD中，需要克服几个挑战。首先，很难证明一个给定的因果关系。 突变，因为许多突变增加了风险，但并不总是产生ASD。其次，这是一项具有挑战性的工作 确定具有自闭症相关表型的动物模型，这些表型在多种遗传背景下都是健壮的。 第三，对负责行为的神经元亚型和回路的有限理解是阻碍 在与疾病相关的细胞背景下研究分子机制。拟议的研究满足了这三个方面的要求 这些挑战中。在F99阶段，具有高度渗透性形式的隐性自闭症的人类家庭导致 通过BAF染色质重塑复合体的神经元特异性亚单位ACTL6B的突变， 确认身份。Actl6b-/-小鼠被测试为ACTL6B突变ASD的模型，并发现表现出与自闭症相关的 在两种遗传背景下的行为，以及与受影响的人类相似的大脑解剖。转录的 对Actl6b-/-皮质培养的分析表明，神经活动诱导的基因在 Actl6b缺失，即使在动作电位被阻断时也是如此。早期反应的高表达 Actl6b-/-神经元中包括AP1转录因子(如Fos、JunB)在内的基因与 AP1位点的染色质可及性和晚期反应基因的活性相关转录变化 暗示早期反应基因的异常激活是潜在的疾病机制。基因组学 与BAF相互作用的BAF复合体、AP1转录因子和NCoR复合体的定位 在皮质组织中，将在野生型和Actl6b-/-神经元中进行研究，以了解是否改变了这些 复合体可能有助于疾病相关的转录变化。为了深入了解受影响的神经元 回路，一种5-羟色胺受体1b(5HT1b)激动剂，在16p11被证明可以拯救社会行为 自闭症小鼠模型(PMID：30089910)被测试并发现可以挽救Act6b-/-小鼠的社会障碍。 自闭症中最常见的BAF亚单位Arid1b的5-羟色胺能神经元特异性缺失导致 同样可以用5HT1b激动剂拯救的小鼠的社会障碍，表明BAF起作用 5-羟色胺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：询问自闭症相关分子机制的神经元群体 控制行为。系统神经科学的博士后培训将支持未来的研究，将 染色质调节蛋白的功能直接影响行为。这项研究支持了 NIH蓝图和大脑倡议通过为自闭症研究提供新的工具并揭示分子和 影响行为的电路机制。