Axon termination of the SAB motor neurons in C. elegans depends on pre- and postsynaptic activity

Abstract Axon termination is a critical step in neural circuit formation, but the contribution of activity from postsynaptic targets to this process remains unclear. Using Caenorhabditis elegans SAB neurons as a model system, we showed that inhibition of muscle activity during a critical period of postembryonic development led to axonal overgrowth and ectopic synapse formation. This effect is mediated by a local retrograde signal and requires neuronal voltage-gated calcium channels (VGCCs) acting cell-autonomously to constrain axon growth. Manipulating SAB neuron excitability demonstrated that increased intrinsic neuronal activity drives overgrowth, while reducing activity suppresses it, establishing a functional link between muscle-derived cues and presynaptic excitability. Transcriptomic analysis and genetic studies further implicate the neuropeptides FLP-18 and NLP-12 as essential modulators of this activity-dependent process. Our findings reveal a temporally and spatially restricted retrograde signaling mechanism in motor neurons, where target activity, neuronal calcium dynamics and neuropeptide signaling cooperate to ensure proper axon termination. These results highlight conserved principles of activity-dependent regulation at neuromuscular junctions and provide a framework for understanding how motor circuits integrate target feedback to sculpt precise connectivity. Competing Interest Statement The authors have declared no competing interest.