Brain Specific RagA Overexpression Triggers Depressive‐Like Behaviors in Mice via Activating ADORA2A Signaling Pathway

Abstract Neuroinflammation hallmarks the pathology of depression although the etiological complexity has not yet been resolved. Previous studies demonstrate that bacterial lipopolysaccharide induces depressive‐like behaviors by activating RagA‐mTOR‐p70S6K signaling pathway. The current project aims to investigate whether and how brain‐specific RagA overexpression triggers depressive‐like behaviors in mice. Full‐length RagA cDNA is cloned into the mammalian expression vector under the control of brain specific promoter, and subsequently overexpressed in the brain of mouse embryos. Indeed, RagA transgenic mice exhibit depressive‐like behaviors and memory impairments. RNA‐seq profiling of the prefrontal cortex (PFC) transcriptome highlights adenosine A2a receptor (ADORA2A) as a key differentially expressed gene (DEG). Western blotting confirms that ADORA2A and phospho‐p70S6K are markedly elevated in RagA transgenic mice. Behavioral assessments demonstrate that ADORA2A inhibitor istradefylline markedly attenuates depressive‐like behaviors. Further metabolomics reveals that N‐acetylserotonin and several depression‐related metabolites are downregulated while proteomic profiling showed that OLIG1 and other proteins are significantly regulated in RagA transgenic mice. Collectively, RagA overexpression alters the expression patterns of signaling proteins and the metabolism of depression‐associated metabolites. RagA may cause depressive‐like behaviors in mice via activating p70S6K/ADORA2A signaling pathway. Thus, RagA‐p70S6K‐ADORA2A signaling pathway may be a target for the development of new antidepressant therapies.