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

项目摘要/摘要 在大脑发育的关键时期，感觉刺激通过以下方式诱导皮质突触重塑 消除不成熟的突触，同时加强其他突触。感觉依赖型突触重构缺陷 被认为是突触成熟延迟和兴奋/抑制失衡的基础，这 与自闭症和其他疾病相关的对感官刺激和社会行为缺陷的敏感 神经精神障碍。然而，关于感觉输入如何驱动突触重构的知识仍然 未被满足。自噬是一种细胞成分的程序化降解和循环过程，通过 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。我们在小鼠模型上的初步发现表明，通过 修剪胡须下调了体感神经元的自噬，增加了突触数量，并 会导致成年后的感觉和社交缺陷。这项研究的目的是记录 自噬在感觉体验诱导的突触重塑中的作用及其在感觉加工和修复中的重要性 健康和疾病方面的社交能力。脆性X综合征(FXS)是自闭症的主要遗传原因， 与过敏症和社交缺陷有关。我们的初步研究发现，自噬在 FXS小鼠躯体感觉皮层提示自噬受损可能与异常有关 突触重构，以及成年FXS小鼠的行为缺陷。这背后的假设是 研究表明，感官刺激诱导自噬，而自噬对经验依赖型突触至关重要 关键时期的重塑，继而影响感觉加工和社会相互作用 成人期。我们进一步推测，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、激活自噬可以挽救这些障碍。我们寻求 从以下几个方面验证这一假设：目标1.记录自噬在感觉经验依赖性中的作用 突触重塑、感觉加工和社会行为。实验将：1)测试感官 关键期剥夺抑制野生型小鼠躯体感觉皮层神经元自噬；2) 确定自噬在关键时期对感觉依赖型突触重塑也是至关重要的 作为成年小鼠正确的感觉处理和社交能力；以及3)决定了模仿感觉 用化学发生方法刺激，DREADDS，拯救自噬，感觉处理和社会 感觉剥夺小鼠之间的相互作用。目的2.研究自噬在感觉加工缺陷中的作用 以及脆性X小鼠的社会互动。实验将：1)检查自噬功能受损是否有因果关系 与脆性X小鼠躯体感觉皮层神经元突触重构缺陷有关；2)研究 药物自噬激活对脆性X小鼠感觉和社会缺陷的影响。

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.