Synapse-enriched m 6 A-modified Malat1 interacts with the novel m 6 A reader, DPYSL2, and is required for fear-extinction memory.

The RNA modification N-methyladenosine (mA) 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 mA RNA-sequencing, we have discovered a distinct population of learning-related mA- modified RNAs at the synapse, which includes the long non-coding RNA metastasis associated lung adenocarcinoma transcript 1 (). RNA immunoprecipitation and mass spectrometry revealed 12 new synapse-specific learning-induced mA readers in the medial prefrontal cortex of male C57/BL6 mice, with mA-modified binding to a subset of these, including CYFIP2 and DPYSL2. In addition, a cell-type- and synapse-specific, and state-dependent, reduction of mA on impairs fear-extinction memory; an effect that likely occurs through a disruption in the interaction between and DPYSL2 and an associated decrease in dendritic spine formation. These findings highlight the critical role of mA in regulating the functional state of RNA during the consolidation of fear-extinction memory, and expand the repertoire of experience- dependent mA readers in the synaptic compartment.We have discovered that learning-induced mA-modified RNA (including the long noncoding RNA, ) accumulates in the synaptic compartment. We have identified several new mA readers that are associated with fear extinction learning and demonstrate a causal relationship between mA-modified and the formation of fear-extinction memory. These findings highlight the role of mA in regulating the functional state of an RNA during memory formation and expand the repertoire of experience-dependent mA readers in the synaptic compartment.