CHANGE OF GRANTEE INSTITUTION: Autophagy Underlies Synaptic Development and ASDs-Related Social Deficits During Critical Period

受资助机构变更：自噬是关键时期突触发育和 ASD 相关社会缺陷的基础

• 批准号: 10356983
• 负责人: Jingqi Yan
• 金额: $ 42.33万
• 依托单位: CLEVELAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356983
• 关键词: CHANGE; GRANTEE; INSTITUTION; Autophagy; Underlies

PROJECT SUMMARY/ABSTRACT During the critical period of brain development, sensory stimuli induce remodeling of cortical synapses by eliminating immature synapses, while strengthening others. Deficits of sensory-dependent synaptic remodeling are thought to underlie the delayed maturation of synapses and imbalance in excitation/inhibition, which underlies hypersensitivity to sensory stimuli and deficits of social behaviors associated with autism and other neuropsychiatric disorders. However, knowledge about how sensory input drives synaptic remodeling is still unmet. Autophagy is a process of programmed degradation and recycling of cellular components via the lysosomal pathway in neurons and other cells and is involved in presynaptic function, synapse elimination and synaptic plasticity in neurons. Our preliminary findings with mouse model indicated that sensory deprivation by trimming whiskers downregulates autophagy in somatosensory neurons, increases the synapse numbers, and leads to sensory and social deficits in adulthood. The objective of this research is to document a role of autophagy in sensory experience-induced remodeling of synapse and its importance on sensory processing and sociability in heathy and diseases. Fragile X syndrome (FXS) is the leading genetic cause of autism, which is associated with hypersensitivity and social deficits. Our preliminary finding that autophagy is decreased in somatosensory cortex of FXS mice suggests that impaired autophagy might be causally related to aberrant synaptic remodeling, as well as the behavioral deficits in adult FXS mice. The underlying hypothesis of this project is that sensory stimuli induce autophagy, and that autophagy is critical to experience-dependent synaptic remodeling during the critical period, which subsequently affect sensory processing and social interactions in adulthood. We further postulate that in FXS mice, while impaired autophagy causes aberrant synaptic remodeling, hypersensitivity and social deficits, activation of autophagy can rescue these disorders. We seek to test this hypothesis in the following: Aim 1. Document a role of autophagy in sensory experience-dependent synapse remodeling, sensory processing and social behaviors. Experiments will: 1) test whether sensory deprivation during the critical period suppress autophagy in somatosensory cortex neurons of wild-type mice; 2) establish that autophagy is critical for sensory-dependent synapse remodeling during the critical period, as well as the correct sensory processing and sociability in adult mice.; and 3) determine that mimicking sensory stimulation with a chemogenetic approach, DREADDS, rescues autophagy, sensory processing and social interactions in sensory-deprived mice. Aim 2. Study the role of autophagy in deficits of sensory processing and social interactions in Fragile X mice. Experiments will: 1) examine whether impaired autophagy is causally related to the deficits of synapse remodeling in somatosensory cortex neurons of Fragile X mice; 2) study the effects of pharmacological autophagy activation on sensory and social deficits in Fragile X mice.

项目摘要/摘要 在大脑发育的关键时期，感觉刺激会通过 消除未成熟的突触，同时加强他人。感觉依赖性突触重塑的缺陷 被认为是突触的延迟成熟和激发/抑制的不平衡的基础， 是对自闭症和其他与自闭症和其他相关的社会行为的缺陷的超敏反应的基础 神经精神疾病。但是，了解感官输入驱动器如何突触重塑仍在 尚未满足。自噬是通过编程降解和通过细胞组件回收的过程 神经元和其他细胞中的溶酶体途径，参与突触前功能，突触消除和 神经元中的突触可塑性。我们使用鼠标模型的初步发现表明，感觉剥夺 修剪胡须下调体感神经元中的自噬，增加突触数量，并 导致成年后的感觉和社会缺陷。这项研究的目的是记录 自动噬在感官体验引起的突触重塑及其对感官处理的重要性和 希西和疾病中的社交性。脆弱的X综合征（FXS）是自闭症的主要遗传原因， 与超敏反应和社会缺陷有关。我们的初步发现自噬减少了 FXS小鼠的体感皮质表明自噬受损可能与异常有关 突触重塑，以及成年FXS小鼠的行为缺陷。这是基本假设 项目是感觉刺激会诱导自噬，并且自噬对于经验依赖性突触至关重要 在关键时期进行重塑，随后会影响感官处理和社交互动 成年。我们进一步假设在FXS小鼠中，自噬受损会导致异常突触 重塑，超敏反应和社会缺陷，自噬的激活可以挽救这些疾病。我们寻求 在以下内容中检验此假设：目标1。记录自噬在感官体验依赖性中 突触重塑，感觉处理和社交行为。实验将：1）测试是否感觉 关键时期的剥夺抑制了野生型小鼠体感皮质神经元的自噬； 2） 确定自噬对于在关键时期内的感觉依赖性突触重塑至关重要 作为成年小鼠的正确感官处理和社交性。 3）确定模仿感官 通过化学生成方法刺激，恐惧，拯救自噬，感觉处理和社交 感觉不足的小鼠的相互作用。目标2。研究自噬在感觉处理缺陷中的作用 和脆弱的X小鼠的社交互动。实验将：1）检查自噬受损是否为因果 与脆弱X小鼠的体感皮质神经元中突触重塑的缺陷有关； 2）研究 药理学自噬激活对脆弱X小鼠感觉和社会缺陷的影响。