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

总结 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：社会 互动和沟通，以及重复行为或限制行为。确诊4次 男孩比女孩更常见。在ASD的大量风险基因座中，蛋白质合成升高具有以下作用： 被认为是一个汇聚的病理机制。ASD与高比例的 在几种负性翻译调节因子基因中存在失活突变的患者，如PTEN，TSC 1， TSC 2和FMR 1。这些突变增加了真核翻译起始因子4 E（eIF 4 E）的可用性， 从而提高选择性mRNA组的翻译。然而，它仍然是未知的， 以及翻译水平的提高如何导致神经回路功能障碍和随后的ASD 行为。我们已经产生了一个敲入小鼠品系，其中eIF 4 E从Rosa 26过表达， 以依赖于Cre的方式存在。我们发现eIF 4 E在小胶质细胞中过表达，而在神经元和 星形胶质细胞，导致ASD样突触和行为畸变，只有在雄性小鼠，包括增加树突状细胞， 脊柱密度、兴奋/抑制失衡、社会互动障碍、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eIF 4 E过表达增加了两种细胞中eIF 4 E的翻译。 但仅在雄性中增加小胶质细胞密度和大小。鉴于小胶质细胞在突触中的重要作用， 在发育过程中，我们发现一些蛋白质合成的增加只在雄性小鼠中改变了小胶质细胞的功能， 进而损害突触发育，从而导致男性偏性ASD。我们将在下面的文章中检验这一假设： 三个具体目标。目的1探讨蛋白质水平升高的分子机制 合成改变小胶质细胞;目的2是了解ASD性二型性的机制， MG 4 E小鼠中的相似表型;目的3是通过以下方式确定小胶质细胞改变如何影响突触发育： 对照和MG 4 E小鼠中树突棘和小胶质细胞的体内动力学成像。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ASD，但也显示小胶质细胞功能障碍是ASD可能病因。它也可能揭示一个 这一机制是ASD强烈的男性偏见的基础，它可以指导ASD创新疗法的策略。 紊乱

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.