METTL3 regulates hippocampal gene transcription via N6-methyladenosine methylation in sevoflurane-induced postoperative cognitive dysfunction mouse

Abstract

Elderly patients are prone to cognitive impairment and memory loss after surgical operations. This perioperative cerebral damage, named postoperative cognitive dysfunction (POCD), is profoundly affected by anesthesia. N6-methyladenosine (m6A) RNA methylation is a widely-studied epigenetic modification to regulate gene expression; however, is has never been studied in POCD. In the present study, elderly POCD mouse models were constructed using sevoflurane, and we observed a compromised global m6A RNA methylation in the mice’s hippocampuses compared with the control. Our RIP-Seq data suggested that 1244 genes (SOX2, SYN1, and BDNF) showed m6A RNA methylation in their 5′UTRs, which was significantly lower than that in the control; while only 56 genes (BACE1 and IL17A) showed m6A RNA methylation in their 5′UTRs, which was significantly higher than that in the control. Unexpectedly, m6A RNA methylation with significant differences in exons, introns, or 3′UTRs was observed in only few genes. Although we failed to find any differences in the expression of m6A-associated proteins, such as m6A “writers”, “erasers”, and “readers”, between the sevoflurane treatment and control groups, RIP-qPCR assays indicated that the binding affinity of METTL3 on mRNA 5′UTRs was particularly weakened in target genes by sevoflurane. Finally, we found that phosphorylation of METTL3 could be reduced by sevoflurane because of the inactivation of the MAPK/ERK pathway. Overall, our study determined that the inactivation of METTL3 in the mouse hippocampus, induced by sevoflurane-mediated MAPK/ERK suppression in vivo , resulted in a perturbation in m6A RNA methylation signals in the pathogenesis of POCD.

Knockdown of METTL16 disrupts learning and memory by reducing the stability of MAT2A mRNA

“…Although the roles of m 6 A methyltransferases in learning and memory have been reported in many studies, ours is the first to demonstrate the function of METTL16 in learning and memory. METTL3, an extensively studied methyltransferase, has been implicated in the formation of hippocampal-dependent memory directly [ 39 ]. Particularly, overexpression of METTL3 in the dorsal hippocampi was shown to have a strategic role in consolidating long-term memory [ 40 ], whereas knockout of METTL3 in the forebrain was shown to have a negative effect during memory consolidation [ 33 , 40 ].…”

Effect of desflurane and sevoflurane on postoperative cognitive dysfunction： A meta-analysis of randomized controlled trials

“…Des urane is a volatile inhalation anesthetic with a minimum MAC of 6%, low blood gas partition coe cient, and rapid onset and elimination, which leads to faster eye opening and extubation times in the des urane group than in the sevo urane group [23]. In animal studies, inhalation of sevo urane in mice resulted in increased apoptosis of hippocampal neurons and induced hippocampal METTL3 inactivation leading to POCD [24,25]. However, short exposure time to sevo urane did not affect cognitive function in mice [26].…”

Knockdown of METTL16 Disrupts Learning and Memory by Reducing the Stability of MAT2A mRNA

“…Although the roles of m 6 A methyltransferases in learning and memory have been reported in many studies, ours is the rst to demonstrate the function of METTL16 in learning and memory. METTL3, an extensively studied methyltransferase, has been shown to have a direct effect on the regulation of hippocampal-dependent memory formation [39]. Particularly, overexpression of METTL3 in the dorsal hippocampi of wild-type mice was found to signi cantly enhance long-term memory consolidation [40], whereas the knockout of METTL3 in the forebrain was found to inhibit memory consolidation [33,40].…”