Neurons can rapidly remodel their synaptic structure and strength in response to neuronal activity, a process crucial for brain function. This study identifies secretory autophagy as a mechanism modulating activity-induced synaptic remodeling in Drosophila. Using an RNAi screen against human disease genes, the researchers found that mutations linked to neurodegenerative and mental health disorders are more likely to affect activity-induced synaptic remodeling than synapse development. While both synapse development and activity-induced remodeling at the fly neuromuscular junction (NMJ) require macroautophagy (autophagy), the pathway bifurcates, differentially impacting development and plasticity. Neuronal activity enhances autophagy activation but suppresses degradative autophagy, driving the pathway toward secretory autophagy. Knockdown of proteins like Snap29, Sec22, or Rab8, involved in secretory autophagy, abolishes activity-induced synaptic remodeling. The study reveals secretory autophagy as a transsynaptic signaling mechanism modulating synaptic plasticity. Secretory autophagy enables rapid communication and coordination of synaptic changes across synapses. Neuronal activity activates secretory autophagy, which is essential for synaptic strengthening post-activity. The findings highlight the role of secretory autophagy in synaptic plasticity and its potential implications for neurological disorders. The study also shows that secretory autophagy is distinct from exosomal release and that neuronal activity enhances lysozyme release through this pathway. These results underscore the importance of secretory autophagy in maintaining synaptic plasticity and functional connectivity in the nervous system.Neurons can rapidly remodel their synaptic structure and strength in response to neuronal activity, a process crucial for brain function. This study identifies secretory autophagy as a mechanism modulating activity-induced synaptic remodeling in Drosophila. Using an RNAi screen against human disease genes, the researchers found that mutations linked to neurodegenerative and mental health disorders are more likely to affect activity-induced synaptic remodeling than synapse development. While both synapse development and activity-induced remodeling at the fly neuromuscular junction (NMJ) require macroautophagy (autophagy), the pathway bifurcates, differentially impacting development and plasticity. Neuronal activity enhances autophagy activation but suppresses degradative autophagy, driving the pathway toward secretory autophagy. Knockdown of proteins like Snap29, Sec22, or Rab8, involved in secretory autophagy, abolishes activity-induced synaptic remodeling. The study reveals secretory autophagy as a transsynaptic signaling mechanism modulating synaptic plasticity. Secretory autophagy enables rapid communication and coordination of synaptic changes across synapses. Neuronal activity activates secretory autophagy, which is essential for synaptic strengthening post-activity. The findings highlight the role of secretory autophagy in synaptic plasticity and its potential implications for neurological disorders. The study also shows that secretory autophagy is distinct from exosomal release and that neuronal activity enhances lysozyme release through this pathway. These results underscore the importance of secretory autophagy in maintaining synaptic plasticity and functional connectivity in the nervous system.