Fear extinction is regulated by the activity of long noncoding RNAs at the synapse. Fear extinction is regulated by the activity of long noncoding RNAs at the synapse

Long noncoding RNAs (lncRNAs) represent a multidimensional class of regulatory molecules involved in many aspects of brain function. Emerging evidence indicates that lncRNAs are expressed at 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 on synaptosomes, we identified a significant number of lncRNAs that accumulate at synapses within the infralimbic prefrontal cortex of adult male C57/Bl6 mice. Among these is 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 dendrites. In addition, we found that cell-type-specific, state-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 the coordination of RNA condensates in the synaptic compartment. Overall design: lncRNA capture sequencing in the synaptic compartment

长链非编码RNA（long noncoding RNAs，lncRNAs）是一类多维度的调控分子，参与大脑功能的诸多环节。日益增多的研究证据表明，lncRNAs可在突触中表达，但目前尚未证实其在该亚细胞区室的活性可直接介导记忆形成过程。本研究通过对突触小体进行lncRNA捕获测序，在成年雄性C57/BL6小鼠的边缘下前额叶皮层的突触中鉴定出大量富集的lncRNAs。其中一种是与应激相关lncRNA Gas5相关的剪接变体。通过RNA免疫沉淀（RNA immunoprecipitation）结合质谱分析与单分子成像，研究发现该Gas5异构体与RNA结合蛋白G3bp2及Caprin1形成复合物，可调控树突中依赖活性的RNA颗粒运输与聚集。此外，我们还发现，对该Gas5变体开展细胞类型特异性、状态依赖性及突触特异性的敲低实验，会导致恐惧消退记忆受损。上述研究结果揭示了一种全新的恐惧消退机制，该机制涉及局部lncRNA活性与突触区室RNA凝聚物协调之间的动态相互作用。整体实验设计：针对突触区室开展lncRNA捕获测序。