Experience-Dependent Accumulation of N6-Methyladenosine in the Prefrontal Cortex Is Associated with Memory Processes in Mice.

The RNA modification N-6-methyladenosine (m(6)A) influences mRNA stability and cell-type-specific developmental programming, and is highly abundant in the adult brain. However, it has not been determined whether m(6)A is dynamically regulated by experience. Based on transcriptome-wide profiling of m(6)A, we report that the level of m(6)A increases in the medial prefrontal cortex (mPFC) of mice in response to behavioral experience. The modulation was enriched near the stop codon of mRNAs, including genes related to neuronal plasticity. In primary cortical neurons, in vitro, modulation of m(6)A by the RNA demethylase FTO influenced the degradation profiles of a subset of transcripts with modulated sites. In vivo, the expression of Fto and the m(6)A methyltransferase, Mettl3 correlated with the observed increase in m(6)A levels post-training. Furthermore, targeted knockdown of FTO in the mPFC led to enhanced consolidation of cued fear memory. Thus, together with its role in early development, the dynamic regulation of m(6)A in the adult brain serves as an important epitranscriptomic mechanism associated with behavioral adaptation.