nlr-1/CNTNAP regulates dopamine circuit structure and foraging behaviors in C. elegans

The neurexin superfamily, consisting of neurexins and Casprs, play important roles in the development, maintenance, function, and plasticity of neuronal circuits. Caspr/ CNTNAP genes are linked to alterations in neuronal circuits and associated with neurodevelopmental and neurodegenerative conditions. Casprs are implicated in multiple neuronal signaling pathways, including dopamine; however, the molecular mechanisms by which Casprs differentially alter specific signaling pathways and downstream behaviors are unclear. We find that the C. elegans Caspr nlr-1 functions in neurons to control foraging behaviors, acting in distinct monoamine neurons to modulate locomotor activity in the presence or absence of food. nlr-1 functions in dopamine neurons to reduce activity in the absence of food, similar to the role of dopamine, and regulates dopamine signaling through D2-like receptors. Furthermore, nlr-1 contributes to proper morphology and presynaptic structure of dopamine neurons, dopamine receptor expression and localization, and the behavioral response to dopamine. We find that nlr-1 similarly regulates another dopamine-dependent behavior, the basal slowing response. Therefore, spatial manipulation of a broadly expressed neuronal gene is sufficient to alter neural circuits and behavior and uncovers important functions masked by global manipulation, highlighting the importance of genetic variation and mechanisms that impact spatial expression of genes to behavior. Removal of nlr-1/CNTNAP from monoamine neurons in C. elegans reveals neuron-specific roles in foraging behaviors, including a critical role for nlr-1 in dopamine neuron morphology, synapse structure, and synapse function that resembles loss of dopamine signaling itself.