M6A facilitates hippocampus‐dependent learning and memory through Ythdf1

Abstract

N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammalian messenger RNAs (mRNAs). While m6A has been shown to mark groups of mRNAs for coordinated degradation in various physiological processes, the physiological relevance of m6A in affecting translation remains to be determined in intact biological systems in vivo. Here we show that, through its reader protein Ythdf1, m6A promotes a pulse of protein synthesis of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory processes. Mice with genetic deletion of the Ythdf1 gene (Ythdf1−/−) exhibit learning and memory defects, as well as impaired hippocampal synaptic transmission and long-term potentiation (LTP). Selective re-expression of Ythdf1 in the hippocampus of adult Ythdf1−/− mice fully rescues the behavioral and synaptic defects, while specific knockdown of Ythdf1 in the adult mouse hippocampus recapitulates the hippocampal deficiency. At the molecular level, transcriptome-wide mapping of m6A on hippocampal mRNAs and RNA-immunoprecipitation sequencing (RIP-seq) of Ythdf1-bound transcripts uncovered key neuronal genes, including those involved in long-term potentiation and synapse assembly, which are subjected to the Ythdf1-dependent regulation. Nascent protein labelling and tethering reporter assays revealed that Ythdf1 is critical for initiating a pulse of protein synthesis of target transcripts 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. Support or Funding Information This study was supported by the National Institute of Health (GM071440 and HG008935 to C.H, NS097206 to H. Song., G-l.M. and C.H., NS047344 to H. Song., R35NS097370 to G-l.M., and DA043361 to X. Zhuang), and National Natural Science Foundation of China (31500866 to T.Z. and 31471077 to X.C.). C.H. is an investigator of the Howard Hughes Medical Institute. T.Z. is sponsored by Shanghai Rising-Star Program. Xingxu Huang is sponsored by Startup Foundation of ShanghaiTech University. Ythdf1 is critical for mouse spatial memory formation, long-term potentiation (LTP), and nascent protein synthesis upon neuronal stimulus. (a) Quadrant time (%) and representative swim paths in Morris water maze probe test of control and Ythdf1-KO mice after training. (b) Induced LTP in control and Ythdf1-KO acute slices. (c) Images of nascent protein (Nascent-P) synthesis in cultured hippocampal neurons infected with AAV-control or AAV-Ythdf1-RNAi before and 4 hrs after KCl depolarization. Ythdf1 promotes translation of m6A-modified transcripts, including LTP and synapse assembly related ones, in response to learning stimulus, thus facilitating synapse strength adequately for a memory to occur. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.