RNA修饰N6-甲基腺嘌呤（m6A）调节核和其他亚细胞区域内RNA与各种RNA结合蛋白的相互作用，并最近被发现参与依赖经验的可塑性、学习和记忆过程。利用m6A RNA测序，我们在突触发现了一类与学习相关的独特m6A修饰的RNA，其中包括长非编码RNA转移相关肺腺癌转录本1（Malat1）。RNA免疫沉淀和质谱分析揭示了12个新的突触特异性学习诱导m6A阅读子，它们存在于雄性C57/BL6小鼠的前额皮质中，m6A修饰的Malat1与其中一部分结合，包括CYFIP2和DPYSL2。此外，Malat1上的m6A修饰有细胞类型、突触特异性，并且与状态相关，在恐惧消退记忆中降低了m6A修饰，这可能通过干扰Malat1与DPYSL2的相互作用和树突棘形成的减少引起。这些发现突显了m6A在恐惧消退记忆巩固期间调节RNA功能状态的关键作用，并扩展了突触区域依赖经验的m6A阅读子的能力。 意义说明：我们发现学习诱导的m6A修饰RNA（包括长非编码RNA Malat1）在突触中积累。我们发现了几个与恐惧消退学习相关的新的m6A阅读子，并证明了m6A修饰的Malat1与恐惧消退记忆形成之间的因果关系。这些发现突显了m6A在记忆形成过程中调节RNA功能状态的作用，并扩展了突触区域依赖经验的m6A阅读子的能力。 版权所有 © 2023 作者们。

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 non-coding RNA metastasis associated lung adenocarcinoma transcript 1 (Malat1). RNA immunoprecipitation and mass spectrometry revealed 12 new synapse-specific learning-induced m6A readers in the medial prefrontal cortex 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 StatementWe 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.Copyright © 2023 the authors.