Abstract：
When exposed to new experiences or changes in the environment, neurons rapidly remodel their synaptic structure and function in a process called activity-induced synaptic remodeling. This process is necessary for transforming transient experiences into stable, lasting memories. The molecular mechanisms underlying acute, activity-dependent synaptic changes are not well understood, partly because processes regulating synaptic plasticity and neurodevelopment are intricately linked. By using an RNAi screen in Drosophila targeting genes associated with human nervous system function, we found that while macroautophagy (referred to as autophagy) is fundamental for both synapse development and synaptic plasticity, activity-induced synaptic remodeling does not rely on genes associated with lysosomal degradation. These findings suggest a requirement for the unconventional secretory autophagy pathway in regulating synaptic plasticity, wherein autophagosomes, instead of fusing with lysosomes for degradation, fuse with the plasma membrane to release their contents extracellularly. To test this hypothesis, we knocked down Sec22, Snap29, and Rab8, molecular components required for secretory autophagy, all of which disrupted structural and functional plasticity. Additionally, by monitoring autophagy, we demonstrated that neuronal activity suppresses degradative autophagy to shift the pathway toward secretory autophagy release. Our work unveils secretory autophagy as a novel trans-synaptic signaling mechanism crucial for activity-induced synaptic remodeling.
摘要：
当暴露于新的体验或环境变化时，神经元在活动诱导的突触重塑过程中迅速重塑其突触结构和功能。这个过程对于将瞬态经验转化为稳定的经验是必要的，持久的记忆。急性潜在的分子机制，活动相关的突触变化没有得到很好的理解，部分原因是调节突触可塑性和神经发育的过程错综复杂。通过在果蝇中使用RNAi筛选与人类神经系统功能相关的靶向基因，我们发现，虽然巨自噬（称为自噬）是突触发育和突触可塑性的基础，活性诱导的突触重塑不依赖于与溶酶体降解相关的基因。这些研究结果表明，在调节突触可塑性时需要非常规分泌性自噬途径，其中自噬体，而不是与溶酶体融合降解，与质膜融合以在细胞外释放其内容物。为了检验这个假设，我们敲除了分泌性自噬所需的分子成分Sec22，Snap29和Rab8，所有这些都破坏了结构和功能的可塑性。此外,通过监测自噬，我们证明了神经元活动抑制降解自噬，从而将途径转向分泌性自噬释放。我们的工作揭示了分泌性自噬作为一种新的跨突触信号机制，对活动诱导的突触重塑至关重要。
