The RNA modification N⁶-methyladenosine (m⁶A) 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 m⁶A RNA-sequencing, we have discovered a distinct population of learning-related m⁶A- 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 m⁶A readers in the mPFC of male C57/BL6 mice, with m⁶A-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 m⁶A 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 highlight the critical role of m⁶A in regulating the functional state of RNA during the consolidation of fear-extinction memory, and expand the repertoire of experience-dependent m⁶A readers in the synaptic compartment.SIGNIFICANCE STATEMENT We have discovered that learning-induced m⁶A-modified RNA (including the long noncoding RNA, Malat1) accumulates in the synaptic compartment. We have identified several new m⁶A readers that are associated with fear extinction learning and demonstrate a causal relationship between m⁶A-modified Malat1 and the formation of fear-extinction memory. These findings highlight the role of m⁶A in regulating the functional state of an RNA during memory formation and expand the repertoire of experience-dependent m⁶A readers in the synaptic compartment.

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