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

项目总结/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层突触的重塑： 消除不成熟的突触同时强化其他突触感觉依赖性突触重塑缺陷 被认为是突触成熟延迟和兴奋/抑制失衡的基础， 是对感觉刺激的超敏反应和与自闭症和其他疾病相关的社会行为缺陷的基础。 神经精神障碍然而，关于感觉输入如何驱动突触重塑的知识仍然是 未满足自噬是一种细胞成分通过细胞内的蛋白质进行程序性降解和再循环的过程。 在神经元和其他细胞中的溶酶体途径，并参与突触前功能，突触消除和 神经元突触的可塑性我们对小鼠模型的初步研究结果表明， 修剪胡须下调了躯体感觉神经元的自噬，增加了突触数量， 导致成年后的感官和社交缺陷。这项研究的目的是记录的作用， 自噬在感觉经验诱发的突触重构中的作用及其在感觉加工和神经功能恢复中的意义 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， 与过敏和社交缺陷有关我们的初步发现，自噬减少， FXS小鼠的躯体感觉皮层表明，受损的自噬可能与异常的 突触重塑，以及成年FXS小鼠的行为缺陷。这背后的假设是 感觉刺激诱导自噬，而自噬对经验依赖性突触的形成至关重要。 重塑在关键时期，随后影响感官处理和社会互动， 成年我们进一步假设，在FXS小鼠中，虽然受损的自噬导致异常的突触 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 在下面的测试这个假设：目的1。记录自噬在感觉经验依赖性 突触重塑、感觉处理和社会行为。实验将：1）测试感官是否 关键期剥夺抑制野生型小鼠躯体感觉皮层神经元的自噬; 2） 确定自噬在关键时期对感觉依赖性突触重塑至关重要，以及 成年老鼠的正确感觉处理和社交能力。以及3）确定模仿感官 用化学发生方法刺激，DREADDS，拯救自噬，感觉处理和社会 在感觉剥夺的小鼠中的相互作用。目标二。研究自噬在感觉加工缺陷中的作用 和社会互动的能力。实验将：1）检查受损的自噬是否是因果关系， 与脆性X小鼠体感皮层神经元突触重塑缺陷有关; 2）研究脆性X小鼠体感皮层神经元突触重塑缺陷与脆性X小鼠体感皮层神经元突触重塑缺陷的关系。 药理学自噬激活对脆性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.