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

Liau, Wei-Siang; Zhao, Qiongyi; Bademosi, Adekunle; Gormal, Rachel S.; Gong, Hao; Marshall, Paul R.; Periyakaruppiah, Ambika; Madugalle, Sachithrani U.; Zajaczkowski, Esmi L.; Leighton, Laura J.; Ren, Haobin; Musgrove, Mason; Davies, Joshua; Rauch, Simone; He, Chuan; Dickinson, Bryan C.; Li, Xiang; Wei, Wei; Meunier, Frédéric A.; Fernández-Moya, Sandra M.

doi:10.6082/j2e7w-0pq74

Published November 22, 2023 | Version v1

Journal article Open

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

1. University of Queensland
2. University of Chicago
3. Wuhan University
4. Bellvitge Institute for Biomedical Research

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.

Notes

Due to the large number of authors, only the first 20 and the University of Chicago authors are included on the above author list. Please download the article for the complete list of authors.

Data availability

Protein network analysis was performed using the STRING protein query database version 11.5 (https://string-db.org). All sequencing data generated in this study have been deposited in the NCBI Gene Expression Omnibus database under the accession code GSE207149. Proteomics data generated in this study have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD046479. All image data generated in this study are available at Figshare (https://doi.org/10.6084/m9.figshare.24431452). The data supporting the findings of this study are available from the corresponding authors upon request. Source data for the figures and supplementary figures are provided as a Source Data file. Source data are provided with this paper.

The sequencing data analysis pipeline and associated custom PERL scripts are available on GitHub (https://github.com/Qiongyi/lncRNA_nucleus_synapse).

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