Potential link between the RagA-mTOR-p70S6K axis and depressive-behaviors during bacterial liposaccharide challenge

Abstract

BackgroundBacterial infection is a potential risk factor for depression. However, little is known about the mechanistic link between bacterial endotoxin and depressive-like behaviors. The aim of the present study was to clarify whether liposaccharide (LPS) could induce depressive-like behaviors in mice via sequentially activating small GTPase RagA, mammalian target of rapamycin (mTOR), and p70S6K.MethodsC57BL/6 N mice were treated with 0.83 mg/kg LPS by intraperitoneal injection for 24 h. The animals were assessed for depressive-like behaviors by forced swim test and tail suspension test. The expression levels of RagA, mTOR, and p70S6K were determined in mice, primary cortical neurons, neural stem cells, and PC12 cells.ResultsLPS effectively induced depressive-like behaviors in mice. Biochemical examination revealed that LPS not only upregulated RagA expression but also activated mTOR/p70S6K pathway in mouse brains. LPS challenge also achieved a similar effect in primary cortical neurons, neural stem cells, and PC12 cells. Following the silencing of RagA expression with specific siRNA, LPS failed to induce mTORC1 translocation to the lysosomal membranes in PC12 cells. These results suggested that LPS might sequentially upregulate RagA and activate mTOR and p70S6K pathways in mice and neural stem cells.ConclusionsThis study for the first time demonstrated that LPS might induce depressive-like behaviors in mice via the upregulation of RagA and subsequent activation of mTOR/p70S6K pathway. Such information may highlight the RagA-mTOR-p70S6K signaling cascade as a novel therapeutic target for the development of new anti-depressant therapeutics.

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“…In liposaccharide-treated mice expressing all phenotypic features of depression, mTOR/p70S6K signaling was elevated in the brain homogenate. Similar findings were observed in in vitro studies using cortical and stem cell neurons [53]. These findings implicate this pathway in the complex pathological mechanism of depression.…”

Botanical Drug Puerarin Ameliorates Liposaccharide‐Induced Depressive Behaviors in Mice via Inhibiting RagA/mTOR/p70S6K Pathways

“…Thus, LPS was used to induce acute inflammation and depressive-like behaviors in mice [ 37 ]. Indeed, we recently found that LPS could cause the depressive-like behaviors in mice via activating RagA/mTOR/p70S6K pathway [ 8 ]. As for the therapy of depression, the conventional antidepressant drugs are challenged by gastrointestinal and sexual side effects [ 38 , 39 ].…”

“…Our group recently revealed that LPS markedly upregulated RagA expression and activated mTORC1 pathway [ 8 ]. RagA forms heterodimers with other isoforms for different functions, for example, RagA/RagB heterodimer for binding GTP and RagC/RagD heterodimer for binding GDP [ 62 ].…”

“…DAPI was used to stain the cell nucleus. The slides were examined under a Carl Zeiss fluorescence microscopy (Jena, Germany) [ 8 ].…”

“…Moreover, bacterial lipopolysaccharide (LPS) induces inflammation and depression in mice [5][6][7]. Our previous study showed that LPS induced depression in mice by upregulating small guanosine triphosphatases (GTPases) RagA expression and subsequently activating mammalian target of rapamycin (mTOR)/p70S6K pathway [8]. Therefore, the RagA/mTOR/p70S6K pathway may be a therapeutic target for the treatment of depression.…”