Developmental cerebellar deficits caused by Chd8 haploinsufficiency

Chd8 单倍体不足引起的小脑发育缺陷

基本信息

批准号：
10373890
负责人：
Diasynou Fioravante
金额：
$ 19.22万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373890
关键词：
Ablation Affect Affective Anatomy Animal Model Behavior Behavioral Brain Brain region Cell Nucleus Cells Cerebellar Cortex Cerebellar Diseases Cerebellar Nuclei Cerebellum Cerebral cortex ChIP-seq Chromatin Remodeling Factor Cognition Cognitive Cognitive deficits Consensus DNA-Binding Proteins Data Development Dimensions Disease model Drug Targeting Electrophysiology (science)Emotions Epigenetic Process Equilibrium Essential Genes Exhibits Functional disorder Future Gene Expression Genes Genetic Genetic Transcription Genomics Hippocampus (Brain)Human Immunohistochemistry Individual Intellectual functioning disability Investigation Language Lead Link Macrocephaly Modeling Molecular Molecular Structure Morphology Mus Mutant Strains Mice Mutation Neuroanatomy Neurodevelopmental Disorder Neurons Output Pathology Patients Pattern Phenotype Physiology Play Population Property Proprioception Prosencephalon Proteins Publishing Purkinje Cells Regulation Reporting Research Rest Role Signal Transduction Structure Synapses Testing Work autism spectrum disorder behavioral outcome behavioral phenotyping biomarker development cell type chromatin remodeling cognitive disability cognitive function de novo mutation drug development experimental study helicase in vitro Model in vivo loss of function mutation motor control mouse model mutant mutant mouse model novel patch clamp patch sequencing postnatal single-cell RNA sequencing social deficits transcriptome sequencing transcriptomics

项目摘要

SUMMARY The role of the cerebellum (CB) in proprioception and fine motor control is well-established, however more recent studies also strongly implicate this structure in higher order cognitive functions such as language, cognitive processing and affective regulation. Despite the tight relationship between these cerebellar functions and Neurodevelopmental Disorders (NDDs) such as Autism Spectrum Disorder (ASD) and Intellectual Disability (ID), the role of non-motor contributions of the CB is often overlooked in NDD research and especially understudied in animal models of these disorders compared to structures such as the cerebral cortex and hippocampus. With the emerging understanding that the CB plays a critical role in higher order brain function and that perturbed cerebellar functioning can lead to ASD and NDD relevant phenotypes, there is strong justification for focus on CB dysfunction in NDD animal models. De novo mutations in the chromatin- remodeling factor CHD8 (Chromodomain-Helicase DNA-binding protein 8) have emerged as a key genetic causal factor strongly associated with ASD and more generally with NDDs. Individuals harboring de novo heterozygous mutations in CHD8 typically present with hallmarks of ASD, cognitive disability, and macrocephaly, with other phenotypes also present in some patients. Multiple mouse Chd8 models have been published (including by our group), with heterozygous mutants exhibiting relevant phenotypes including macrocephaly and behavioral deficits. To date, animal models of pathology associated with CHD8 mutation have focused on the forebrain, and in particular the cerebral cortex. In published and preliminary studies, we identified altered structure of the deep cerebellar nuclei and evidence of altered cerebellar anatomy and physiology in mice harboring heterozygous Chd8 mutation. We hypothesize that cerebellar impact of Chd8 mutation contributes to higher order cognitive and behavioral pathology. Here, we propose initial work towards testing this model, defining the impact of Chd8 haploinsufficiency on cerebellar structure and function across anatomical, genomic, and electrophysiological dimensions. In Aim 1, we will test CB sensitivity to Chd8 haploinsufficiency with regard to patterning and cell identity. In Aim 2, we will test for phenotypes at the electrophysiological, transcriptomic and morphologic level in cerebellar neurons. These experiments will establish impacts of heterozygous Chd8 mutation on the mouse CB, linking neuroanatomy, neuronal function, and signaling. These studies will provide critical evidence for future work defining specific phenotypes associated with heterozygous Chd8 ablation in the CB and towards building a circuit level understanding of how Chd8 mutations impact connectivity within the CB and between the CB and other structures. If successful, this work will lead to new avenues of research on cerebellar dysfunction in NDDs and ASD by linking a high confidence and top priority gene with cellular, molecular, and structural deficits in the CB.

概括小脑 (CB) 在本体感觉和精细运动控制中的作用已得到充分证实，但更多最近的研究也强烈暗示这种结构与高阶认知功能（例如语言、认知处理和情感调节。尽管这些小脑功能之间存在紧密的关系和神经发育障碍 (NDD)，例如自闭症谱系障碍 (ASD) 和智力障碍残疾（ID），即 CB 非运动贡献的作用在 NDD 研究中经常被忽视，与大脑等结构相比，这些疾病的动物模型尤其缺乏研究皮质和海马体。随着人们越来越认识到 CB 在更高阶中发挥着关键作用大脑功能以及小脑功能紊乱可导致 ASD 和 NDD 相关表型，这是关注 NDD 动物模型中 CB 功能障碍的有力理由。染色质的从头突变重塑因子 CHD8（染色质结构域解旋酶 DNA 结合蛋白 8）已成为关键遗传因子与自闭症谱系障碍（ASD）密切相关的因果因素，更普遍的是与NDDs密切相关。从头窝藏个人 CHD8 的杂合突变通常表现为自闭症谱系障碍 (ASD)、认知障碍和巨头畸形，一些患者还存在其他表型。多个小鼠 Chd8 模型已被发表（包括我们小组），杂合突变体表现出相关表型，包括大头畸形和行为缺陷。迄今为止，与CHD8突变相关的病理动物模型重点关注前脑，特别是大脑皮层。在已发表的和初步的研究中，我们确定了小脑深部核团结构的改变以及小脑解剖结构改变的证据携带杂合 Chd8 突变的小鼠的生理学。我们假设 Chd8 对小脑的影响突变有助于更高阶的认知和行为病理学。在这里，我们提出初步工作为了测试这个模型，定义 Chd8 单倍体不足对小脑结构的影响和跨解剖学、基因组和电生理学维度的功能。在目标 1 中，我们将测试 CB 在模式和细胞身份方面对 Chd8 单倍体不足的敏感性。在目标 2 中，我们将测试小脑神经元电生理、转录组和形态学水平的表型。这些实验将确定杂合 Chd8 突变对小鼠 CB 的影响，将神经解剖学、神经元功能和信号传导。这些研究将为未来定义具体的工作提供关键证据与 CB 中杂合 Chd8 消融相关的表型以及构建电路水平了解 Chd8 突变如何影响 CB 内以及 CB 与其他物质之间的连接结构。如果成功，这项工作将为 NDD 和小脑功能障碍的研究开辟新途径。 ASD 通过将高置信度和最优先的基因与 CB 中的细胞、分子和结构缺陷联系起来。