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

• DOI: 10.1101/2023.10.06.560931
• Publication Date: 2023-10-09T12:21:49Z
• Authors: Yen-Ching Chang; Yuan Gao; Joo Yeun Lee; Jennifer Langen; Karen T. Chang

AbstractThe 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. Here, using an RNAi screen inDrosophilaagainst genes affecting nervous system functions in humans, we uncouple cellular processes important for synaptic plasticity from 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 further demonstrate that neuronal activity stimulates 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 novel trans-synaptic signaling mechanism modulating structural plasticity.