Cortical Serotonin Type 2A Receptor Activation Shields Episodic-like Memories from Retroactive Interference in Rodents

The acquisition of temporally proximate information can impair the brain’s ability to consolidate earlier experiences, resulting in retroactive interference (RI). Recognition-based behavioral paradigms are well-suited for investigating RI in rodents, particularly those involving sequential learning episodes. The medial prefrontal cortex (mPFC) integrates multimodal information relevant to the regulation of memory interference and is strongly modulated by the serotonergic system. Serotonin 2A receptors (5-HT2AR), which are densely expressed in the mPFC, have been shown to influence the retrieval of competing object-recognition memories. However, their role in other phases of memory processing, particularly in modulating RI, remains unclear. Using a novel object recognition task designed to induce RI, combined with pharmacological manipulation of 5-HT2AR, we demonstrate that RI specifically impairs the object-related component of memory. Moreover, serotonin signaling through 5-HT2AR is necessary to prevent RI. Strikingly, the activation of 5-HT2AR before retrieval can rescue the expression of memories affected by RI, suggesting that RI may not erase memory traces but rather hinder access to them.