PKA orchestrates long-range lysosomal vesicle transport during synaptic maintenance

Bidirectional long-distance transport of organelles is crucial for communication between the cell body and synapses, yet how this transport is regulated during synapse formation, maintenance, and plasticity remains unclear. In the Aplysia sensory neuron (SN)-motor neuron system, which mediates the gill-siphon withdrawal reflex, we demonstrate that synapse maintenance coincides with a sustained decrease in retrograde lysosomal vesicle (LV) transport in SNs. This reduction becomes evident three days after synapse formation, in contrast to anterograde mitochondrial transport, which increases within 12 h. Serotonin-induced, learning-related synapse formation further suppresses retrograde lysosomal transport within 24 h, while boosting anterograde mitochondrial transport as early as 1 h post-exposure. A pharmacological screen implicates PKA as a key regulator of retrograde LV transport during synapse maintenance. These results reveal organelle-specific, temporally distinct regulation of long-distance transport in synapse formation, maintenance, and plasticity.