Cdc42-Dependent Forgetting Regulates Repetition Effect in Prolonging Memory Retention

• Single-session training leads to ARM formation and Cdc42 activation
• Repeated learning prolongs ARM through inhibition of Cdc42-mediated forgetting
• Cdc42 inhibition mimics repeated learning sessions in prolonging ARM retention
• Increased Cdc42 activity abolishes repetition-induced ARM extension

SummaryRepeated learning is used daily and is a powerful way to improve memory. A fundamental question is how multiple learning trials add up to improve memory. While the major studies so far of such a repetition effect have emphasized the strengthening of memory formation, the current study reveals a molecular mechanism through suppression of forgetting. We find that single-session training leads to formation of anesthesia-resistant memory (ARM) and then activation of the small G protein Cdc42 to cause decay or forgetting of ARM within 24 hr. Repetition suppresses the activation of Cdc42-dependent forgetting, instead of enhancing ARM formation, leading to prolonged ARM. Consistently, inhibition of Cdc42 activity through genetic manipulation mimicked the repetition effect, while repetition-induced ARM improvement was abolished by elevated Cdc42 activity. Thus, only the first session in repetitive training contributes to ARM formation, while the subsequent sessions are devoted not to acquiring information but to inhibiting forgetting.

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