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

• DOI: 10.1002/advs.202404188
• Publication Date: 2024-10-07T14:41:27Z
• Authors: Jia Zhao; Yilu Sun; Yibin Feng; Jianhui Rong
• Keywords: ADORA2A; Science; depression; Q; RagA; molecular mechanism; p70S6K; Research Article

Abstract Neuroinflammation hallmarks the pathology of depression although 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 in mice. Full‐length cDNA is cloned into mammalian expression vector under control brain specific promoter, subsequently overexpressed mouse embryos. Indeed, transgenic mice exhibit memory impairments. RNA‐seq profiling prefrontal cortex (PFC) transcriptome highlights adenosine A2a receptor (ADORA2A) as a key differentially expressed gene (DEG). Western blotting confirms ADORA2A phospho‐p70S6K are markedly elevated Behavioral assessments inhibitor istradefylline attenuates behaviors. Further metabolomics reveals N‐acetylserotonin several depression‐related metabolites downregulated while proteomic showed OLIG1 other proteins significantly regulated Collectively, alters patterns metabolism depression‐associated metabolites. may cause via p70S6K/ADORA2A Thus, RagA‐p70S6K‐ADORA2A pathway be target for development new antidepressant therapies.