M6A facilitates hippocampus-dependent learning and memory through YTHDF1.

Abstract

SummaryN6-methyladenosine (m6A), the most prevalent internal RNA modification on mammalian messenger RNAs (mRNAs), regulates fates and functions of modified transcripts through m6A-specific binding proteins1–5. m6A is abundant in the nervous system and modulates various neural functions6–11. While m6A marks groups of mRNAs for coordinated degradation in various physiological processes12–15, the relevance of m6A in mRNA translation remains largely unknown in vivo. Here we show that, through its binding protein Ythdf1, m6A promotes protein synthesis of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory. Mice with genetic deletion of Ythdf1 (Ythdf1-KO) exhibit learning and memory defects as well as impaired hippocampal synaptic transmission and long-term potentiation. Ythdf1 re-expression in the hippocampus of adult Ythdf1-KO mice rescues behavioral and synaptic defects, while hippocampus-specific acute knockdown of Ythdf1 or Mettl3, the catalytic component of m6A methyltransferase complex, recapitulates the hippocampal deficiency. Transcriptome-wide mapping of Ythdf1 binding sites and m6A sites on hippocampal mRNAs uncovered key neuronal genes. Nascent protein labeling and tether reporter assays in hippocampal neurons revealed that Ythdf1 enhances protein synthesis in a neuronal-stimulus-dependent manner. Collectively, our results uncover a pathway of mRNA m6A methylation in learning and memory, which is mediated through Ythdf1 in response to stimuli.