N6-methyladenosine RNA modification of glutamatergic neurons is associated with contextual fear discrimination

Abstract

Fear memory overgeneralization is a hallmark of many stress-related disorders, especially posttraumatic stress disorder. The neurobiology of fear memory generalization and discrimination involves a series of interplays between molecular and cellular factors, the mechanisms of which remain largely unexplored. N⁶-methyladenosine (m⁶A) of RNA is a reversible and dynamically regulated posttranscriptional modification with especially high levels in mammalian brain. In the present study, we found a positive correlation of m⁶A methylation abundance with accurate threat discrimination ability in response to fear memory. In addition, the methyltransferase Mettl3 levels showed a significant positive correlation with fear discrimination ability, suggesting a vital role of hippocampal METTL3-mediated m⁶A modification on contextual fear memory discrimination. By generating cell type-specific Mettl3 deficient mouse models, we demonstrated that METTL3 expressed in hippocampal glutamatergic neurons, but not in GABAergic neurons or astrocytes is specifically involved in fear discrimination and memory generalization, although Mettl3 depletion failed to affect the capability of developing fear memory. Taken together, our study revealed that m⁶A tagging is a crucial regulator of fear memory generalization through finetuning the activity of glutamatergic neurons.

Keywords: Astrocytes; GABAergic neurons; Glutamatergic neurons; Memory discrimination; Memory generalization; RNA methylation.