m6A facilitates hippocampus-dependent learning and memory through YTHDF1.

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 proteins1-5. In the nervous system, m⁶A is abundant and modulates various neural functions6-11. Whereas m⁶A marks groups of mRNAs for coordinated degradation in various physiological processes12-15, 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. Neuronal stimulation induces protein translation of m⁶A-methylated neuronal mRNAs facilitated by YTHDF1, and this process contributes to learning and memory. [ABSTRACT FROM AUTHOR]