Natural Variation in a Dendritic Scaffold Protein Remodels Experience-Dependent Plasticity by Altering Neuropeptide Expression

The extent to which behavior is shaped by experience varies between individuals. Genetic differences contribute to this variation, but the neural mechanisms are not understood. Here, we dissect natural variation in the behavioral flexibility of two Caenorhabditis elegans wild strains. In one strain, a memory of exposure to 21% O2 suppresses CO2-evoked locomotory arousal; in the other, CO2 evokes arousal regardless of previous O2 experience. We map that variation to a polymorphic dendritic scaffold protein, ARCP-1, expressed in sensory neurons. ARCP-1 binds the Ca2+-dependent phosphodiesterase PDE-1 and co-localizes PDE-1 with molecular sensors for CO2 at dendritic ends. Reducing ARCP-1 or PDE-1 activity promotes CO2 escape by altering neuropeptide expression in the BAG CO2 sensors. Variation in ARCP-1 alters behavioral plasticity in multiple paradigms. Our findings are reminiscent of genetic accommodation, an evolutionary process by which phenotypic flexibility in response to environmental variation is reset by genetic change. •Behavioral flexibility varies across Caenorhabditis and C. elegans wild isolates•A natural polymorphism in ARCP-1 underpins inter-individual variation in plasticity•ARCP-1 is a dendritic scaffold protein localizing cGMP signaling machinery to cilia•Disrupting ARCP-1 alters behavioral plasticity by changing neuropeptide expression Individuals can vary in their capacity to adapt their behavior to changes in the environment. Beets et al. identify a natural genetic polymorphism that modifies behavioral flexibility by altering the neuromodulatory output of primary sensory neurons.