Serotonin signaling in the rat prefrontal cortex is required for Retrieval-Induced Forgetting

Forgetting is a ubiquitous phenomenon actively promoted in many species. The act of remembering some experiences can cause forgetting of others in both humans and rats. We previously found that when rats retrieve a memory to guide exploration, it reduces later retention of other competing memories encoded in that environment. As with humans, this retrieval-induced forgetting (RIF) relies on prefrontal control processes, is competition-dependent, and cue-independent. RIF is thought to be driven by inhibitory control signals from the prefrontal cortex that target areas where memories are stored. Serotonin plays a crucial role in behaviors requiring high cognitive demand, including memory processes, partly through its modulation of prefrontal cortex activity. However, its potential involvement in regulating active forgetting remains unexplored. Here, in male and female rats performing a task known to induce RIF, we pharmacologically manipulated serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors and their downstream effectors in the medial prefrontal cortex (mPFC). Our findings reveal a specific role for prefrontal serotonin signaling in RIF. Whereas 5-HT2C receptor manipulation had no effect, activating 5-HT1A or blocking 5-HT2A receptors in the mPFC abolished RIF. By contrast, activating 5-HT2A receptors promotes RIF under conditions in which it is normally reduced. Further analyses identified the PI3K/AKT pathway as a downstream effector of 5-HT2A receptor signaling, suggesting a specific molecular mechanism through which serotonin modulates inhibitory control over memory. These results uncover a previously unrecognized serotonergic modulation of adaptive forgetting, identifying specific receptor subtypes that link prefrontal serotonin signaling to inhibitory control over memory competition. Significance statement Forgetting is an essential, active process that helps the brain stay flexible and focused. In both humans and animals, remembering one thing can lead to forgetting competing memories, a phenomenon called retrieval-induced forgetting (RIF). Our research shows that serotonin, a neurotransmitter best known for its role in mood, also actively regulates which memories are forgotten. In rats, we found that serotonin signaling in the prefrontal cortex regulates adaptive forgetting: 5-HT2A receptor signaling promotes RIF, whereas activation of 5-HT1A receptors disrupts it. We further identified PI3K/AKT signaling as a key downstream effector of 5-HT2A receptor activation in this process. These findings matter because the mechanisms of active forgetting remain poorly understood, and their disruption may contribute to psychopathological conditions.