Molecular and cellular basis for autism spectrum disorders caused by exacerbated translation

加剧翻译引起的自闭症谱系障碍的分子和细胞基础

基本信息

批准号：
10704718
负责人：
GAVIN R RUMBAUGH
金额：
$ 53.66万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-03 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704718
关键词：
Affinity Chromatography Androgens Apoptosis Appearance Astrocytes Behavior Behavior Disorders Behavioral Cd68 Cephalic Cognitive deficits Data Set Dendritic Spines Development Diagnosis Disease Estradiol Etiology Eukaryotic Initiation Factors FMR1 Female Functional disorder Genes Gonadal Hormones Gonadal Steroid Hormones Hormone Receptor Image Impairment In Vitro Induced Mutation Injury Innovative Therapy Knock-in Mouse Label Lead Messenger RNA Microglia Molecular Monitor Morphology Mouse Strains Mus Mutation Neurodevelopmental Disorder Neuronal Dysfunction Neurons PTEN gene Pathologic Patients Perinatal Phenotype Process Proliferating Protein Biosynthesis Proteins Research Project Grants Ribosomes Role Sex Chromosomes Social Interaction Synapses TSC1 gene TSC2 gene Testing Testis Testosterone Translating Translations Vertebral column Viral X Chromosome Y Chromosome autism spectrum disorder barrel cortex boys brain cell cell growth cell motility communication behavior comparison control density dosage effective therapy girls imaging study in vivo in vivo imaging insight male neural circuit overexpression repetitive behavior response risk variant sex sex determination sexual dimorphism sry Genes transcriptome transcriptome sequencing

项目摘要

Summary Autism spectrum disorder (ASD) is a neurodevelopmental disorder with deficits in two core domains: social interaction and communication, and repetitive behaviors or restrictive behaviors. It is diagnosed four times more frequently in boys than in girls. Among a large number of risk loci for ASD, elevated protein synthesis has been recognized as a converging pathological mechanism. ASD is associated with a high percentage of patients with inactivating mutations in genes for several negative translation regulators, such as PTEN, TSC1, TSC2 and FMR1. These mutations increase the availability of eukaryotic translation initiation factor 4E (eIF4E), consequently elevating translation of a selective group of mRNAs. However, it remains unknown in which type of brain cells and how elevated translation leads to dysfunction of neural circuits and subsequently ASD behaviors. We have generated a knock-in mouse strain in which eIF4E is overexpressed from the Rosa26 locus in a Cre-dependent manner. We found that eIF4E overexpression in microglia, but not neurons or astrocytes, led to ASD-like synaptic and behavioral aberrations only in male mice, including increased dendritic spine density, excitation/inhibition imbalance, social interaction impairment, increased repetitive behavior, and selective cognitive deficits. We further found that microglial eIF4E overexpression elevated translation in both sexes but only increased microglial density and size in males. Given critical roles of microglia in synapse development, we posit that elevated synthesis of some proteins alters microglial functions only in male mice, which in turn impairs synapse development and thereby male-biased ASD. We will test this hypothesis in the following three specific aims. Aim 1 is to investigate the molecular mechanism by which elevated protein synthesis alters microglia; Aim 2 is to understand the mechanism underlying the sexual dimorphism of ASD- like phenotypes in MG4E mice; Aim 3 is to determine how microglial alterations impact synapse development by imaging in vivo dynamics of dendritic spines and microglia in control and MG4E mice. This research project will not only provide insights into the pathological mechanism by which mutations in negative translation regulators lead to ASD, but also show microglial dysfunction as a possible etiology of ASD. It may also uncover a mechanism that underlies the strong male bias of ASD, which could guide strategies for innovative therapies of the disorder.

概括自闭症谱系障碍 (ASD) 是一种神经发育障碍，在两个核心领域存在缺陷：社交互动和沟通，以及重复行为或限制行为。已确诊四次男孩比女孩更常见。在自闭症谱系障碍 (ASD) 的大量风险位点中，蛋白质合成升高被认为是一种聚合的病理机制。自闭症谱系障碍（ASD）与高比例的患有多种负翻译调节因子基因失活突变的患者，例如 PTEN、TSC1、 TSC2 和 FMR1。这些突变增加了真核翻译起始因子 4E (eIF4E) 的可用性，因此提高了一组选择性 mRNA 的翻译。但目前尚不清楚属于哪种类型脑细胞的变化以及翻译水平升高如何导致神经回路功能障碍以及随后的自闭症谱系障碍 (ASD) 行为。我们已经生成了一种敲入小鼠品系，其中 eIF4E 从 Rosa26 中过度表达基因座以 Cre 依赖的方式。我们发现 eIF4E 在小胶质细胞中过度表达，但在神经元或星形胶质细胞仅在雄性小鼠中导致 ASD 样突触和行为异常，包括树突增加脊柱密度、兴奋/抑制失衡、社交互动障碍、重复行为增加，以及选择性认知缺陷。我们进一步发现小胶质细胞 eIF4E 过度表达增强了两种细胞中的翻译性别，但仅增加男性的小胶质细胞密度和大小。鉴于小胶质细胞在突触中的关键作用在发育过程中，我们认为某些蛋白质的合成增加只会改变雄性小鼠的小胶质细胞功能，这反过来又会损害突触发育，从而导致男性偏向的自闭症谱系障碍 (ASD)。我们将在遵循三个具体目标。目标 1 是研究蛋白质升高的分子机制合成改变小胶质细胞；目标 2 是了解自闭症谱系障碍 (ASD) 性别二态性的潜在机制类似于 MG4E 小鼠的表型；目标 3 是确定小胶质细胞改变如何影响突触发育对照小鼠和 MG4E 小鼠的树突棘和小胶质细胞的体内动态成像。该研究项目将不仅提供了对负翻译调节因子突变的病理机制的见解导致自闭症谱系障碍，但也表明小胶质细胞功能障碍是自闭症谱系障碍的可能病因。它还可能揭示一个自闭症谱系障碍（ASD）强烈的男性偏见背后的机制，可以指导自闭症谱系障碍（ASD）的创新治疗策略紊乱。