Exposure to constant light impairs cognition with FTO inhibition and m6A-dependent TrκB repression in mouse hippocampus

N6-methyladenosine (m(6)A) mRNA methylation plays a role in various brain functions. Exposure to chronic constant light (CCL) has been reported to impair cognition, yet whether the underlying mechanism involves m(6)A remains unknown. In this study, mice exposed to CCL for 3 weeks show impaired cognitive behavior, which was associated with increased m(6)A level in hippocampus. Accordingly, the m(6)A demethylase FTO was inhibited while the methyltransferases METTL3, METTL14 and WTAP, as well as the reader protein YTHDF2, were elevated in the hippocampus of CCL-exposed mice. CCL exposure significantly activated hippocampal expression of circadian regulator cryptochrome 1 and 2 (CRY1 and 2). Meanwhile, hippocampal neurogenesis was impaired with suppression of BDNF/Tr kappa B/ERK pathway. To further delineate the signaling pathway and the role of m(6)A, we altered the expression of CRY1/2 in hippocampus neuron cells. CRY1/2 overexpression inhibited FTO and increased m(6)A levels, while CRY1/2 knockdown led to opposite results. Luciferase reporter analysis further confirmed CRY1/2-induced FTO suppression. Furthermore, FTO knockdown increased m(6)A on 3'UTR of Tr kappa B mRNA, and decreased Tr kappa B mRNA stability and Tr kappa B protein expression, in a YTHDF2-dependent manner. These results indicate that CCL-activated CRY1/2 causes transcriptional inhibition of FTO, which suppresses Tr kappa B expression in hippocampus via m(6)A-dependent post-transcriptional regulation and contributes to impaired cognitive behavior in mice exposed to constant light. (C) 2021 Elsevier Ltd. All rights reserved.