Identification of secretory autophagy as a mechanism modulating activity- induced synaptic remodeling

• 成果类型: Article
• 署名作者: Chang, Yen-Ching; Gao, Yuan; Lee, Joo Yeun; Langen, Jennifer; Chang, Karen T.
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of Southern California; University of Southern California
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8633
• DOI: 10.1073/pnas.2315958121
• 发表日期: 2024-04-16
• 关键词: activity-dependent ubiquitination; structural plasticity; drosophila; GROWTH; maturation; lysozyme; PATHWAY; SYSTEM; MODEL; glua1

摘要

The ability of neurons to rapidly remodel their synaptic structure and strength in response to neuronal activity is highly conserved across species and crucial for complex brain functions. However, mechanisms required to elicit and coordinate the acute, activity- dependent structural changes across synapses are not well understood, as neurodevelopment and structural plasticity are tightly linked. Here, using an RNAi screen in Drosophila against genes affecting nervous system functions in humans, we uncouple cellular processes important for synaptic plasticity and synapse development. We find mutations associated with neurodegenerative and mental health disorders are 2 - times more likely to affect activity- induced synaptic remodeling than synapse development. We report that while both synapse development and activity- induced synaptic remodeling at the fly NMJ require macroautophagy (hereafter referred to as autophagy), bifurcation in the autophagy pathway differentially impacts development and synaptic plasticity. We demonstrate that neuronal activity enhances autophagy activation but diminishes degradative autophagy, thereby driving the pathway towards autophagy-based secretion. Presynaptic knockdown of Snap29, Sec22, or Rab8, proteins implicated in the secretory autophagy pathway, is sufficient to abolish activity- induced synaptic remodeling. This study uncovers secretory autophagy as a transsynaptic signaling mechanism modulating synaptic plasticity.