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

Summary

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.