Synapse-Enriched m6 A-Modified Malat1 Interacts with the Novel m6 A Reader, DPYSL2, and Is Required for Fear-Extinction Memory.

The RNA modification N6 -methyladenosine (m6 A) regulates the interaction between RNA and various RNA binding proteins within the nucleus and other subcellular compartments and has recently been shown to be involved in experience-dependent plasticity, learning, and memory. Using m6 A RNA-sequencing, we have discovered a distinct population of learning-related m6 A- modified RNAs at the synapse, which includes the long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (Malat1). RNA immunoprecipitation and mass spectrometry revealed 12 new synapse-specific learning-induced m6 A readers in the mPFC of male C57/BL6 mice, with m6 A-modified Malat1 binding to a subset of these, including CYFIP2 and DPYSL2. In addition, a cell type- and synapse-specific, and state-dependent, reduction of m6 A on Malat1 impairs fear-extinction memory; an effect that likely occurs through a disruption in the interaction between Malat1 and DPYSL2 and an associated decrease in dendritic spine formation. These findings high-light the critical role of m6 A in regulating the functional state of RNA during the consolidation of fear-extinction memory, and expand the repertoire of experience-dependent m6 A readers in the synaptic compartment. [ABSTRACT FROM AUTHOR]