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

基本信息

  • 批准号:
    10356983
  • 负责人:
  • 金额:
    $ 42.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目总结/文摘

项目成果

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Jingqi Yan其他文献

Jingqi Yan的其他文献

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{{ truncateString('Jingqi Yan', 18)}}的其他基金

Sensory experience-dependent autophagy induces synapse remodeling during critical period
感觉体验依赖性自噬诱导关键期突触重塑
  • 批准号:
    10043875
  • 财政年份:
    2020
  • 资助金额:
    $ 42.33万
  • 项目类别:

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