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

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.