NMDAR mediated dynamic changes in m6A inversely correlates with neuronal translation

Epitranscriptome modifications are crucial in translation regulation and essential for maintaining cellular homeostasis. N6 methyladenosine (m(6)A) is one of the most abundant and well-conserved epitranscriptome modifications, which is known to play a pivotal role in diverse aspects of neuronal functions. However, the role of m(6)A modifications with respect to activity-mediated translation regulation and synaptic plasticity has not been studied. Here, we investigated the role of m(6)A modification in response to NMDAR stimulation. We have consistently observed that 5 min NMDAR stimulation causes an increase in eEF2 phosphorylation. Correspondingly, NMDAR stimulation caused a significant increase in the m(6)A signal at 5 min time point, correlating with the global translation inhibition. The NMDAR induced increase in the m(6)A signal is accompanied by the redistribution of the m(6)A marked RNAs from translating to the non-translating pool of ribosomes. The increased m(6)A levels are well correlated with the reduced FTO levels observed on NMDAR stimulation. Additionally, we show that inhibition of FTO prevents NMDAR mediated changes in m(6)A levels. Overall, our results establish RNA-based molecular readout which corelates with the NMDAR-dependent translation regulation which helps in understanding changes in protein synthesis.

Automated summary

Epitranscriptome modifications, particularly N6 methyladenosine (m(6)A), play a crucial role in translation regulation and synaptic plasticity. This study reveals that m(6)A modification is involved in NMDAR-dependent translation regulation and that its levels are correlated with changes in protein synthesis.