Enhanced Protein Synthesis and Hippocampus-Dependent Memory via Inhibition of YTHDF2-Mediated m⁶A mRNA Degradation

N⁶-methyladenosine (m⁶A) modification intricately regulates mRNA transportation, localization, and translation, significantly influencing learning and memory processes. However, the specific role of YT521-B homology (YTH) domain-containing family protein 2 (YTHDF2)-mediated m⁶A mRNA degradation in learning and memory remains elusive. Utilizing a forebrain-specific conditional knockout mice model, it is discovered that the absence of YTHDF2 impedes the decay of m⁶A-modified mRNAs, resulting in heightened synaptic transmission in hippocampal neurons and improved hippocampus-dependent learning and memory. Unexpectedly, an increase in activity-dependent protein synthesis is also observed. Reintroduction of YTHDF2 expression or reduction of its downstream target, Semaphorin 4B (SEMA4B), in the hippocampus reverses the enhanced memory in conditional knockout mice, while augmenting YTHDF2 in wild-type mice impairs memory performance. These findings underscore the pivotal role of YTHDF2-mediated mRNA degradation in regulating learning and memory processes.