Developmental cerebellar deficits caused by Chd8 haploinsufficiency

Chd8 单倍体不足引起的小脑发育缺陷

• 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
• 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

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）在本体感受和精细运动控制中的作用是完善的，但是更多 最近的研究还强烈暗示了这种结构以高阶认知功能（例如语言）， 认知处理和情感调节。尽管这些小脑功能之间有密切的关系 和神经发育障碍（NDD），例如自闭症谱系障碍（ASD）和智力 残疾（ID），在NDD研究中经常忽略CB的非运动贡献的作用 与大脑等结构相比，在这些疾病的动物模型中特别研究了 皮层和海马。随着新兴的了解，CB在高阶中起着至关重要的作用 大脑功能和扰动的小脑功能会导致ASD和NDD相关的表型 在NDD动物模型中关注CB功能障碍是有力的理由。染色质中的从头突变 - 重塑因子CHD8（染色体蛋白酶螺旋酶DNA结合蛋白8）已成为关键遗传 因果因素与ASD密切相关，并且与NDD更普遍地相关。藏有从头开始的个人 CHD8中的杂合突变通常具有ASD的标志，认知障碍和 大畸形，一些患者也存在其他表型。多个鼠标CHD8模型已经 发表（包括我们的小组），杂合突变体表现出相关表型，包括 脑畸形和行为缺陷。迄今为止，与CHD8突变相关的病理动物模型 专注于前脑，尤其是大脑皮层。在已发表和初步研究中，我们 鉴定出深小脑核的结构发生了改变，以及小脑解剖学改变的证据和 具有杂合CHD8突变的小鼠的生理学。我们假设CEREBELLAR对CHD8的影响 突变有助于高阶认知和行为病理。在这里，我们提出了初步工作 要测试该模型，定义CHD8单倍性对小脑结构和 跨解剖学，基因组和电生理维度的功能。在AIM 1中，我们将测试CB 对图案和细胞身份的CHD8单倍体不足的敏感性。在AIM 2中，我们将测试 小脑神经元的电生理，转录组和形态学水平的表型。这些 实验将建立杂合CHD8突变对小鼠CB的影响，并将神经解剖学联系起来， 神经元功能和信号传导。这些研究将为未来定义特定的工作提供关键证据 与CB中的杂合CHD8消融相关的表型并朝着电路水平建立 了解CHD8突变如何影响CB内以及CB之间的连通性 结构。如果成功，这项工作将导致NDDS和 通过将高置信度和最高优先基因与CB中的细胞，分子和结构缺陷联系起来，ASD。