Post-transcriptional modifications of RNA, such as RNA methylation, can epigenetically regulate behavior, for instance learning and memory. However, it is unclear whether RNA methylation plays a critical role in the pathophysiology of major depression disorder (MDD). Here, we report that expression of the fat mass and obesity associated gene (FTO), an RNA demethylase, is downregulated in the hippocampus of patients with MDD and mouse models of depression. Suppressing
Fto
expression in the mouse hippocampus results in depression-like behaviors in adult mice, whereas overexpression of FTO expression leads to rescue of the depression-like phenotype. Epitranscriptomic profiling of N6-methyladenosine (m
6
A) RNA methylation in the hippocampus of
Fto
knockdown (KD),
Fto
knockout (cKO), and FTO-overexpressing (OE) mice allows us to identify adrenoceptor beta 2 (
Adrb2
) mRNA as a target of FTO. ADRB2 stimulation rescues the depression-like behaviors in mice and spine loss induced by hippocampal
Fto
deficiency, possibly via the modulation of hippocampal SIRT1 expression by c-MYC. Our findings suggest that FTO is a regulator of a mechanism underlying depression-like behavior in mice.
Post-transcriptional modification of RNA can contribute to regulating behavior. Here, the authors show that modulating the expression of
Fto
results in epitranscriptomic changes in the mouse hippocampus associated with depression-like behavior.