Long noncoding RNAs (lncRNAs) represent a multidimensional class of regulatory molecules that are involved in many aspects of brain function. Emerging evidence indicates that lncRNAs are localized to the synapse; however, a direct role for their activity in this subcellular compartment in memory formation has yet to be demonstrated. Using lncRNA capture-seq, we identified a specific set of lncRNAs that accumulate in the synaptic compartment within the infralimbic prefrontal cortex of adult male C57/Bl6 mice. Among these was a splice variant related to the stress-associated lncRNA, Gas5. RNA immunoprecipitation followed by mass spectrometry and single-molecule imaging revealed that this Gas5 isoform, in association with the RNA binding proteins G3BP2 and CAPRIN1, regulates the activity-dependent trafficking and clustering of RNA granules. In addition, we found that cell-type-specific, activity-dependent, and synapse-specific knockdown of the Gas5 variant led to impaired fear extinction memory. These findings identify a new mechanism of fear extinction that involves the dynamic interaction between local lncRNA activity and RNA condensates in the synaptic compartment.

长非编码 RNA (lncRNA) 代表了一类多维的调节分子，涉及大脑功能的许多方面。新的证据表明 lncRNA 定位于突触；然而，它们在这个亚细胞区室中的活性在记忆形成中的直接作用尚未得到证实。使用 lncRNA capture-seq，我们鉴定了一组特定的 lncRNA，它们在成年雄性 C57/Bl6 小鼠边缘下前额皮质内的突触室中积累。其中包括与应激相关lncRNA相关的剪接变体Gas5 。 RNA 免疫沉淀、质谱分析和单分子成像表明， Gas5亚型与 RNA 结合蛋白 G3BP2 和 CAPRIN1 结合，调节 RNA 颗粒的活性依赖性运输和聚集。此外，我们发现细胞类型特异性、活动依赖性和突触特异性的Gas5变体敲低会导致恐惧消退记忆受损。这些发现确定了一种新的恐惧消退机制，涉及局部 lncRNA 活性和突触区室中 RNA 凝聚体之间的动态相互作用。