Discovery of synapse-specific RNA N6-methyladenosine readers associated with the consolidation of fear extinction memory

Summary The RNA modification N 6 -methyladenosine (m 6 A) 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 m 6 A-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 m 6 A readers in the medial prefrontal cortex of male C57/B6 mice. m 6 A RNA-sequencing also revealed a unique population of learning-related m 6 A-modified RNAs at the synapse, which includes a variant of the long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 ( Malat1 ). m 6 A-modified Malat1 binds to a subset of novel m 6 A 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 m 6 A-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 m 6 A-modified Malat1 and select RBPs in the synaptic compartment.