Dynamic regulation of mRNA acetylation at synapses by learning and memory

Abstract

N4-acetylcytidine (ac4C) is the only RNA acetylation modification identified in eukaryotes and has recently been recognized as an epitranscriptomic mechanism regulating mRNA stability and translation efficiency. However, the function and regulation of mRNA acetylation in the brain remain largely unknown. In this study, the presence of ac4C in mRNA was demonstrated by dot blot analysis and UPLC-MS/MS. A transcriptome-wide mapping of ac4C was performed in the hippocampus of adult mice trained in the Morris water maze, a protocol for learning and memory. Notably, the protein levels of N-acetyltransferase 10 (NAT10), the ac4C writer, increased at synapses following memory formation but returned to baseline levels after forgetting. Moreover, the downregulation of NAT10-mediated N4-acetylcytidine in mRNA in the mouse hippocampus using the Cre/LoxP strategy resulted in impaired synaptic plasticity and deficits in learning and memory. These findings underscore the dynamics and functions of synaptic mRNA acetylation during learning and memory, providing novel insights into the epitranscriptomic regulation of brain function. The ac4C epitranscriptome dataset in mouse hippocampus is accessible via the website (http://ac4Catlas.com/).