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

Wei-Siang Liau (), Qiongyi Zhao, Adekunle Bademosi, Rachel S. Gormal, Hao Gong, Paul R. Marshall, Ambika Periyakaruppiah, Sachithrani U. Madugalle, Esmi L. Zajaczkowski, Laura J. Leighton, Haobin Ren, Mason Musgrove, Joshua Davies, Simone Rauch, Chuan He, Bryan C. Dickinson, Xiang Li, Wei Wei, Frédéric A. Meunier, Sandra M. Fernández-Moya, Michael A. Kiebler, Balakumar Srinivasan, Sourav Banerjee, Michael Clark, Robert C. Spitale and Timothy W. Bredy ()
Additional contact information
Wei-Siang Liau: The University of Queensland
Qiongyi Zhao: The University of Queensland
Adekunle Bademosi: The University of Queensland
Rachel S. Gormal: The University of Queensland
Hao Gong: The University of Queensland
Paul R. Marshall: The University of Queensland
Ambika Periyakaruppiah: The University of Queensland
Sachithrani U. Madugalle: The University of Queensland
Esmi L. Zajaczkowski: The University of Queensland
Laura J. Leighton: The University of Queensland
Haobin Ren: The University of Queensland
Mason Musgrove: The University of Queensland
Joshua Davies: The University of Queensland
Simone Rauch: The University of Chicago
Chuan He: The University of Chicago
Bryan C. Dickinson: The University of Chicago
Xiang Li: Zhongnan Hospital of Wuhan University
Wei Wei: Zhongnan Hospital of Wuhan University
Frédéric A. Meunier: The University of Queensland
Sandra M. Fernández-Moya: Biomedical Centre, Ludwig Maximilian University of Munich
Michael A. Kiebler: Biomedical Centre, Ludwig Maximilian University of Munich
Balakumar Srinivasan: National Brain Research Centre
Sourav Banerjee: National Brain Research Centre
Michael Clark: University of Melbourne
Robert C. Spitale: The University of California
Timothy W. Bredy: The University of Queensland

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43535-1

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