This study investigates the mechanisms underlying activity-induced synaptic remodeling in *Drosophila* using an RNAi screen against human disease genes. The authors found that mutations associated with neurodegenerative and mental health disorders are more likely to affect activity-induced synaptic remodeling than synapse development. They identified that while both processes require macroautophagy, the autophagy pathway differentially impacts development and synaptic plasticity. Neuronal activity enhances autophagy activation but diminishes degradative autophagy, driving the pathway towards secretory autophagy. Knockdown of proteins involved in the secretory autophagy pathway, such as Snap29, Sec22, and Rab8, abolishes activity-induced synaptic remodeling. The study reveals that secretory autophagy acts as a transsynaptic signaling mechanism, modulating synaptic plasticity. This mechanism is crucial for rapid coordination of synaptic changes across synapses in the fly neuromuscular junction (NMJ).This study investigates the mechanisms underlying activity-induced synaptic remodeling in *Drosophila* using an RNAi screen against human disease genes. The authors found that mutations associated with neurodegenerative and mental health disorders are more likely to affect activity-induced synaptic remodeling than synapse development. They identified that while both processes require macroautophagy, the autophagy pathway differentially impacts development and synaptic plasticity. Neuronal activity enhances autophagy activation but diminishes degradative autophagy, driving the pathway towards secretory autophagy. Knockdown of proteins involved in the secretory autophagy pathway, such as Snap29, Sec22, and Rab8, abolishes activity-induced synaptic remodeling. The study reveals that secretory autophagy acts as a transsynaptic signaling mechanism, modulating synaptic plasticity. This mechanism is crucial for rapid coordination of synaptic changes across synapses in the fly neuromuscular junction (NMJ).