Memory formation relies on rapid and stable changes in transcription and translation (Davis and Squire, 1984, Duvarci et al., 2008). Regulation of transcription during memory formation is relatively well described, with epigenetic changes playing a key role (Zovkic et al., 2013). Learning-induced changes in translation are equally vital (Hernandez and Abel, 2008), but mechanisms of regulating translation during memory formation are less understood. Epitranscriptomics, the study of post-transcriptional modifications to RNA, has emerged as a novel regulator of translation. The most researched epitranscriptomic modification is methylation of the 6′ position of adenosine (m6A) (Desrosiers et al., 1974), which regulates many RNA functions, including localization of mRNA to specific cellular compartments and mRNA translation and degradation (Wang, 2014, Zhou, 2015, Meyer, 2015, Dominissini, 2012)

m6A is deposited on RNA by the m6A writing complex, canonically composed of Mettl3, Mettl14, and WTAP (Ping, 2014, Liu, 2014, Schwartz, 2014). m6A is installed co-transcriptionally in the nucleus (Huang, 2019) and is removed by “eraser” proteins that can be found throughout the cell (Tang, 2018, Jia, 2011, Walters, 2017), thus allowing regulation of m6A marks in distinct cellular compartments. The demethylase FTO (Fat-mass and Obesity associated) was the first characterized demethylase of m6A (Jia, 2011) that has since been shown to also demethylate the related m6Am bi-methylation (methylation occurs in the m6A location, and in the ribose backbone) (Mauer, 2017, Mauer, 2019). FTO has been implicated in a variety of neuronal functions, from neuronal development (Li, 2017) to memory formation (Walters, 2017, Zhou, 2015, Widagdo, 2016), suggesting that active regulation of mRNA methylation is a critical feature of memory formation (Leonetti, 2020). Our previous work (Walters, 2017), and that of others (Widagdo, 2016), have demonstrated that acute loss of FTO in the hippocampus of male mice improved memory formation on aversive memory tasks, implying that FTO acts as a memory suppressor. However, both stress (Zhou, 2015, Engel, 2018) and sex determination (Lence, 2016, Haussmann, 2016, Sui, 2020) are regulated by m6A, so it is unclear if the role of FTO and m6A in memory is specific for stressful/aversive tasks or if its effects differ in male and female mice as a sex specific function. Here, we seek to understand if FTO regulates non-aversive memory tasks, and if these effects differ in male and female mice.

Our data show that in contrast to improved performance on aversive memory tasks (Walters, 2017), FTO depletion in area CA1 of the hippocampus impaired memory on the object-location memory (OLM) task while no effect was seen on performance in the novel object recognition (NOR) task. Additionally, loss of FTO impaired OLM memory specifically in male mice, with no changes observed in memory performance in female mice after FTO depletion. Together, this work reveals a more nuanced role for FTO in memory formation, whereby its effect on memory varies with respect to the type of task and sex of the animal.