N6-methyladenosine (m6A), the most prevalent internal RNA modification on mammalian messenger RNAs, regulates the fates and functions of modified transcripts through m6A-specific binding proteins1,2,3,4,5. In the nervous system, m6A is abundant and modulates various neural functions6,7,8,9,10,11. Whereas m6A marks groups of mRNAs for coordinated degradation in various physiological processes12,13,14,15, the relevance of m6A for mRNA translation in vivo remains largely unknown. Here we show that, through its binding protein YTHDF1, m6A promotes protein translation of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory. Mice with genetic deletion of Ythdf1 show learning and memory defects as well as impaired hippocampal synaptic transmission and long-term potentiation. Re-expression of YTHDF1 in the hippocampus of adult Ythdf1-knockout mice rescues the behavioural and synaptic defects, whereas hippocampus-specific acute knockdown of Ythdf1 or Mettl3, which encodes the catalytic component of the m6A methyltransferase complex, recapitulates the hippocampal deficiency. Transcriptome-wide mapping of YTHDF1-binding sites and m6A sites on hippocampal mRNAs identified key neuronal genes. Nascent protein labelling and tether reporter assays in hippocampal neurons showed that YTHDF1 enhances protein synthesis in a neuronal-stimulus-dependent manner. In summary, YTHDF1 facilitates translation of m6A-methylated neuronal mRNAs in response to neuronal stimulation, and this process contributes to learning and memory.
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High-throughput sequencing data can be accessed in the Gene Expression Omnibus under accession number GSE106607. Source data for bar graphs and box-plots in Figures and Extended Data Figures are provided in separate excel files.
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This study was supported by the National Key R&D Program of China (2016YFA0500903 to X.H.), the National Institute of Health (HG008935 and GM113194 to C.H.; DA043361 to X. Zhuang), the National Natural Science Foundation of China (31500866 to T.Z. and 31471077 to X.C.), the Simons Foundation Autism Research Initiative (SFARI) to H. Song, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF) to G.-l.M. C.H. is an investigator of the Howard Hughes Medical Institute. T.Z. is sponsored by the Shanghai Rising-Star Program. X.H. is sponsored by the Startup Foundation of ShanghaiTech University. X. Zhang is sponsored by Zhejiang Public Welfare Technology Application Research Project (2018C37118). We thank P. Cao, and X. Wang for discussions; Z. Qiu and T. Cheng for help with primary neuron culture; M. Wu for suggestions on proteomics data analyses; and J. Tauler, P. J. Hsu, and A. C. Zhu for editing help.