YTHDF2 in dentate gyrus is the m⁶A reader mediating m⁶A modification in hippocampus-dependent learning and memory

N⁶-methyladenosine (m⁶A) has been demonstrated to regulate learning and memory in mice. To investigate the mechanism by which m⁶A modification exerts its function through its reader proteins in the hippocampus, as well as to unveil the specific subregions of the hippocampus that are crucial for memory formation, we generated dentate gyrus (DG)-, CA3-, and CA1-specific Ythdf1 and Ythdf2 conditional knockout (cKO) mice, respectively. Surprisingly, we found that only the DG-specific Ythdf2 cKO mice displayed impaired memory formation, which is inconsistent with the previous report showing that YTHDF1 was involved in this process. YTHDF2 controls the stability of its target transcripts which encode proteins that regulate the elongation of mossy fibers (MF), the axons of DG granule cells. DG-specific Ythdf2 ablation caused MF overgrowth and impairment of the MF-CA3 excitatory synapse development and transmission in the stratum lucidum. Thus, this study identifies the m⁶A reader YTHDF2 in dentate gyrus as the only regulator that mediates m⁶A modification in hippocampus-dependent learning and memory.