The role of the m6A/m demethylase FTO in memory is both task and sex-dependent in mice

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS ACS Applied Bio Materials Pub Date : 2024-02-23 DOI:10.1016/j.nlm.2024.107903
Amanda M. Leonetti , Isabella R. Galluzzo , Timothy A.D. McLean , Gilda Stefanelli , Fiona Ramnaraign , Samuel Holm , Stephen M. Winston , Isaiah L. Reeves , Mark A. Brimble , Brandon J. Walters
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Abstract

Formation of long-term memories requires learning-induced changes in both transcription and translation. Epitranscriptomic modifications of RNA recently emerged as critical regulators of RNA dynamics, whereby adenosine methylation (m6A) regulates translation, mRNA stability, mRNA localization, and memory formation. Prior work demonstrated a pro-memory phenotype of m6A, as loss of m6A impairs and loss of the m6A/m demethylase FTO improves memory formation. Critically, these experiments focused exclusively on aversive memory tasks and were only performed in male mice. Here we show that the task type and sex of the animal alter effects of m6A on memory, whereby FTO-depletion impaired object location memory in male mice, in contrast to the previously reported beneficial effects of FTO depletion on aversive memory. Additionally, we show that female mice have no change in performance after FTO depletion, demonstrating that sex of the mouse is a critical variable for understanding how m6A contributes to memory formation. Our study provides the first evidence for FTO regulation of non-aversive spatial memory and sexspecific effects of m6A, suggesting that identification of differentially methylated targets in each sex and task will be critical for understanding how epitranscriptomic modifications regulate memory.

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m6A/m 去甲基化酶 FTO 在小鼠记忆中的作用取决于任务和性别
长期记忆的形成需要学习引起的转录和翻译变化。RNA 的外转录修饰最近成为 RNA 动态的关键调节因子,其中腺苷甲基化(m6A)调节翻译、mRNA 稳定性、mRNA 定位和记忆形成。之前的研究证明了 m6A 有助于记忆形成的表型,因为缺失 m6A 会损害记忆形成,而缺失 m6A/m 去甲基化酶 FTO 则会改善记忆形成。重要的是,这些实验只关注厌恶性记忆任务,而且只在雄性小鼠中进行。在这里,我们发现任务类型和动物性别会改变 m6A 对记忆的影响,其中 FTO 缺失会损害雄性小鼠的物体位置记忆,这与之前报道的 FTO 缺失对厌恶性记忆的有利影响截然不同。此外,我们还发现雌性小鼠在缺失 FTO 后表现没有变化,这表明小鼠的性别是了解 m6A 如何促进记忆形成的关键变量。我们的研究首次证明了 FTO 对非厌恶性空间记忆的调控以及 m6A 的性别特异性效应,这表明识别不同性别和任务中的不同甲基化靶标对于理解表转录组修饰如何调控记忆至关重要。
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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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