METTL3-mediated N6-methyladenosine mRNA modification enhances long-term memory consolidation

Abstract

The formation of long-term memory is critical for learning ability and social behaviors of humans and animals, yet its underlying mechanisms are largely unknown. We found that the efficacy of hippocampus-dependent memory consolidation is regulated by METTL3, an RNA N6-methyladenosine (m6A) methyltransferase, through promoting the translation of neuronal early-response genes. Such effect is exquisitely dependent on the m6A methyltransferase function of METTL3. Depleting METTL3 in mouse hippocampus reduces memory consolidation ability, yet unimpaired learning outcomes can be achieved if adequate training was given or the m6A methyltransferase function of METTL3 was restored. The abundance of METTL3 in wild-type mouse hippocampus is positively correlated with learning efficacy, and overexpression of METTL3 significantly enhances long-term memory consolidation. These findings uncover a direct role of RNA m6A modification in regulating long-term memory formation, and also indicate that memory efficacy difference among individuals could be compensated by repeated learning.

A neural m6A/YTHDF pathway is required for learning and memory inDrosophila

“…Recent studies have highlighted neuronal functions of mammalian m 6 A pathway factors (Du et al, 2019;Widagdo and Anggono, 2018). There is a growing appreciation that mouse mutants of multiple components in the m 6 A RNA-modification machinery affect learning and memory (Koranda et al, 2018;Walters et al, 2017;Widagdo et al, 2016;Zhang et al, 2018c). Here, we provide substantial evidence that, in Drosophila, neural m 6 A is critical for short-term memory (STM).…”

“…Recent studies showed that m 6 A pathway is required for learning and memory in mice Zhang et al, 2018c). We used a classical aversive conditioning paradigm to test Drosophila m 6 A mutants for deficits in short-term memory (henceforth 'STM' or 'memory').…”

“…In mice, the m 6 A writer Mettl3 is reported to enhance long term memory consolidation, potentially by promoting the expression of genes such as Arc, c-Fos and others (Zhang et al, 2018c). Another study found that Mettl14 is required for LTM formation and neuronal excitability (Koranda et al, 2018).…”

m6A-epitranscriptome modulates memory strength

“…Recently, mRNA transcript stability and translation was shown to critically depend on N 6 -methyladenosine (m 6 A) modification 6-8 , a process bidirectionally regulated upon learning by the m 6 A methylase METTL3 and the demethylase FTO [6][7][8] . In the current study, Zhang et al 2 investigated whether m 6 A modification of mRNA might influence translation of IEGs and memory strength. The authors knocked out METTL3 in postnatal forebrain, including hippocampus, using mice expressing a conditional allele of METTL3 in a CaMK2-Cre background.…”

“…To overcome these challenges, there has been a need for identification of relevant endogenous molecular processes that modulate memory strength after acquisition. The paper by Zhang et al 2 makes an important contribution towards this objective.…”