Abstract
The formation of long-lasting memories requires coordinated changes in gene expression and protein synthesis. Although many studies implicate DNA modifications (DNA methylation, histone modifications) in memory formation, the contributions of RNA modifications remain largely unexplored. Here we investigated the role of mRNA methylation in hippocampal-dependent memory formation in mice. RNA modifications are highly dynamic and readily reversible. Methyltransferases add a methyl group to mRNA while demethylases remove methyl groups. Here we focused on examining the role of the best characterized RNA demethylase, FTO (fat mass and obesity-associated) in memory. We observed that FTO is expressed in the nuclei, dendrites and near dendritic spines of mouse dorsal hippocampal CA1 neurons. Next, we found that contextual fear conditioning transiently (0.5 h) decreased Fto levels in these neurons, with the largest decrease in FTO observed near synapses. The decrease in FTO observed shortly after contextual fear conditioning suggests that FTO normally constrains memory formation. To directly test this, we artificially decreased FTO levels in dorsal hippocampus of otherwise normal (wild-type) mice by microinjecting before training a single herpes simplex virus (HSV) vector expressing either CRISPR/Cas9 or shRNA targeted against Fto. Decreasing FTO using either method specifically enhanced contextual fear memory. Together, these results show the importance of FTO during memory formation and, furthermore, implicate mRNA modification and epi-transcriptomics as novel regulators of memory formation.