Forgetting memories is important for animals to properly respond to continuously changing environments. To elucidate the mechanisms of forgetting, we used one of the behavioral plasticities of C. elegans hermaphrodite, olfactory adaptation to an attractive odorant, diacetyl, as a simple model of learning. In C. elegans, the TIR-1/JNK-1 pathway accelerates forgetting of olfactory adaptation by facilitating neural secretion from AWC sensory neurons. In this study, to identify the downstream effectors of the TIR-1/JNK-1 pathway, we conducted a genetic screen for suppressors of the gain-of-function mutant of
tir-1 (
ok1052), which shows excessive forgetting. Our screening showed that three proteins, a membrane protein, MACO-1, a receptor tyrosine kinase, SCD-2, and its putative ligand, HEN-1, regulated forgetting downstream of the TIR-1/JNK-1 pathway. We further demonstrated that MACO-1 and SCD-2/HEN-1 functioned in parallel genetic pathways, and only MACO-1 regulated forgetting of olfactory adaptation to isoamyl alcohol, which is an attractive odorant sensed by different types of sensory neurons. In olfactory adaptation, odor-evoked Ca(2+) responses in olfactory neurons are attenuated by conditioning and recovered thereafter. Ca(2+) imaging study revealed that this attenuation is sustained longer in
maco-1 and
scd-2 mutant animals than in wild-type animals like the TIR-1/JNK-1 pathway mutants. Furthermore, temporal silencing by histamine-gated chloride channels revealed that the neuronal activity of AWC neurons after conditioning is important for proper forgetting. Taken together, we propose that distinct signaling pathways, which have each specific function, may coordinately and temporally regulate forgetting by controlling sensory responses.SIGNIFICANCE STATEMENTActive forgetting is an important process to understand the whole mechanisms of memories, and it has been recently reported that the non-cell autonomous regulations are required for proper forgetting in invertebrates. We found that the non-cell autonomous regulations of forgetting of olfactory adaptation in C. elegans hermaphrodite, is regulated by three conserved proteins, a membrane protein, MACO-1, a receptor tyrosine kinase, SCD-2, and its ligand, HEN-1. MACO-1 and SCD-2/HEN-1 coordinately accelerate forgetting by controlling sensory responses in parallel. Furthermore, temporal regulation of the neuronal activity is important for the proper forgetting. Taken together, we suggest that multiple pathways may coordinately and temporally regulate forgetting through control of sensory responses, and this study lead to understand forgetting in higher organisms.