Fto in the hippocampus mediates depression-like behaviors

Dynamic and reversible RNA methylation has emerged as a new layer of epigenetic regulation of behaviors such as learning and memory; however, whether RNA methylation plays a critical role in the pathophysiology of depression is unclear. Here, we report that expression of the fat mass and obesity associated gene (FTO), a primary RNA demethylase, is downregulated in the hippocampi of both major depressive disorder (MDD) patients and mouse models of depression. Suppressing Fto expression in the hippocampus induces depression-like behaviors in mice, while elevating its expression leads to antidepressant effects. Epitranscriptomic profiling of N6-methyladenosine (m6A) RNA methylation in the hippocampi of Fto knockdown (KD), Fto knockout (cKO), and Fto-overexpressing (OE) mice identified adrenoceptor beta 2 (Adrb2) mRNA as a target of Fto. Adrb2 stimulation reverses the depression-like behaviors and spine loss induced by hippocampal Fto deficiency, possibly via the modulation of hippocampal Sirt1 expression by c-Myc. These findings reveal that Fto in the hippocampus mediates depression-like behaviors and highlight the importance of reversible RNA methylation in driving depression.