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

N6-methyladenosine (m⁶A) 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 m⁶A remains unknown. In this study, mice exposed to CCL for 3 weeks show impaired cognitive behavior, which was associated with increased m⁶A level in hippocampus. Accordingly, the m⁶A 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/TrκB/ERK pathway. To further delineate the signaling pathway and the role of m⁶A, we altered the expression of CRY1/2 in hippocampus neuron cells. CRY1/2 overexpression inhibited FTO and increased m⁶A levels, while CRY1/2 knockdown led to opposite results. Luciferase reporter analysis further confirmed CRY1/2-induced FTO suppression. Furthermore, FTO knockdown increased m⁶A on 3'UTR of TrκB mRNA, and decreased TrκB mRNA stability and TrκB protein expression, in a YTHDF2-dependent manner. These results indicate that CCL-activated CRY1/2 causes transcriptional inhibition of FTO, which suppresses TrκB expression in hippocampus via m⁶A-dependent post-transcriptional regulation and contributes to impaired cognitive behavior in mice exposed to constant light.