1. Fear extinction is regulated by the activity of long noncoding RNAs at the synapse.
- Author
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Liau, Wei-Siang, Zhao, Qiongyi, Bademosi, Adekunle, Gormal, Rachel, Gong, Hao, Marshall, Paul, Periyakaruppiah, Ambika, Madugalle, Sachithrani, Zajaczkowski, Esmi, Leighton, Laura, Ren, Haobin, Musgrove, Mason, Davies, Joshua, Rauch, Simone, He, Chuan, Dickinson, Bryan, Li, Xiang, Wei, Wei, Meunier, Frédéric, Fernández-Moya, Sandra, Kiebler, Michael, Srinivasan, Balakumar, Banerjee, Sourav, Clark, Michael, Bredy, Timothy, and Spitale, Robert
- Subjects
Mice ,Male ,Animals ,Fear ,RNA ,Long Noncoding ,Extinction ,Psychological ,Prefrontal Cortex ,Synapses - Abstract
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.
- Published
- 2023