LAUSR

Significance Neurons are endowed with the capacity to rapidly remodel their synaptic structure and strength in response to varying stimuli. This process, known as activity-induced synaptic remodeling, is crucial for the brain’s ability to transform transient experiences into long-term memory. However, signaling mechanisms used by neurons to coordinate the appropriate synaptic changes remain unclear. To this end, we conducted a genetic screen in Drosophila against human disease orthologs. We found perturbations in genes associated with neurodegenerative and mental health disorders disproportionately disrupt activity-induced synaptic remodeling compared to synapse development. Furthermore, we found that an autophagy-based release pathway is crucial for activity-induced synaptic remodeling while degradative autophagy maintains synapse development. These findings reveal secretory autophagy as a paradigm regulating synaptic plasticity.