LncRNA Dleu2 regulates fear extinction memory through Celf2-driven synaptic plasticity

Long noncoding RNAs (lncRNAs) are diverse regulators that shape many aspects of brain function. Nonetheless, their role in the mechanisms underlying fear extinction memory remains insufficiently explored. We profiled lncRNAs following the RNA capture-seq in the infralimbic prefrontal cortex (ILPFC) and identified the processed-transcript lncRNA deleted in lymphocytic leukemia-2 (Dleu2). The knockdown of Dleu2 by antisense oligonucleotide (ASO) impaired extinction memory, which demonstrated an essential role of Dleu2 in this process. To elucidate the underlying mechanism, CHIRP-seq and ATAC-seq analyses demonstrated an increased binding of Dleu2 within the intronic region of Celf2, accompanied by enhanced chromatin accessibility. This modulation subsequently promotes the transcription of Celf2, a critical gene involved in synaptic plasticity. Functionally, Celf2 knockdown in ILPFC recapitulated the fear extinction memory deficit and reduced the number of dendritic spines. Together, these results indicate that lncRNA Dleu2 may serve as a potential therapeutic entry point for memory-related disorders.