PT  - JOURNAL ARTICLE
AU  - Sachithrani U. Madugalle
AU  - Wei-Siang Liau
AU  - Qiongyi Zhao
AU  - Xiang Li
AU  - Hao Gong
AU  - Paul R. Marshall
AU  - Ambika Periyakaruppiah
AU  - Esmi L. Zajackowski
AU  - Laura J. Leighton
AU  - Haobin Ren
AU  - Mason Musgrove
AU  - Joshua Davies
AU  - Simone Rauch
AU  - Chuan He
AU  - Bryan C. Dickinson
AU  - Lee Fletcher
AU  - Barbora Fulopova
AU  - Stephen R. Williams
AU  - Robert C. Spitale
AU  - Timothy W. Bredy
TI  - Discovery of synapse-specific RNA N6-methyladenosine readers associated with the consolidation of fear extinction memory
AID  - 10.1101/2022.06.07.495230
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.06.07.495230
4099  - http://biorxiv.org/content/early/2022/06/09/2022.06.07.495230.short
4100  - http://biorxiv.org/content/early/2022/06/09/2022.06.07.495230.full
AB  - The RNA modification N6-methyladenosine (m6A) is critically involved in the regulation of gene activity underlying experience-dependent plasticity, and is necessary for the functional interplay between RNA and RNA binding proteins (RBPs) in the nucleus. However, the complete repertoire of m6A-modified RNA interacting RBPs in the synaptic compartment, and whether they are involved in fear extinction, have yet to be revealed. Using RNA immunoprecipitation followed by mass spectrometry, we discovered 12 novel, synapsespecific, learning-induced m6A readers in the medial prefrontal cortex of male C57/B6 mice. m6A RNA-sequencing also revealed a unique population of learning-related m6A-modified RNAs at the synapse, which includes a variant of the long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (Malat1). m6A-modified Malat1 binds to a subset of novel m6A readers, including cytoplasmic FMR1 interacting protein 2 (CYFIP2) and dihydropyrimidase-related protein 2 (DPYSL2) and a cell-type-specific, state-dependent, and synapse-specific reduction in m6A-modified Malat1 disrupts the interaction between Malat1 and DPYSL2 and impairs fear extinction. The consolidation of fear-extinction memory therefore relies on an interaction between m6A-modified Malat1 and select RBPs in the synaptic compartment.Competing Interest StatementThe authors have declared no competing interest.