The neuromuscular junction (NMJ) is crucial for understanding the fundamentals of synaptic transmission and activity. Various modulators operate within neuronal circuits, from sensory to motor neurons, to influence synaptic transmission at the NMJ. This study sheds light on the regulation of sensory-evoked cholinergic neurotransmission at motor neurons orchestrated by CASY-1, the mammalian calsyntenin orthologue. We report that the increased excitation-inhibition (E-I) ratio at the NMJ in mutants is likely due to its interactions with neuromodulators in sensory neurons. We explored the intricate genetic interactions of CASY- 1 with the neuropeptide FLP-21 and its receptor, NPR-1, both of which display simultaneous alterations in cholinergic signaling at the NMJ. Through genetic, pharmacological, and bioimaging-based experiments, we proposed a mechanism by which CASY-1 potentially interacts with the neuropeptide-carrying vesicles to regulate synaptic transmission. The nematode serves as an ideal model system for this study, enabling detailed insights into neuromodulatory mechanisms in the neuronal circuit.
