Astrocyte atrophy induced by L-PGDS/PGD2/Src signaling dysfunction in the central amygdala mediates postpartum depression.

BACKGROUND: Postpartum depression (PPD) is a serious psychiatric disorder that has significantly adverse impacts on maternal health. Metabolic abnormalities in the brain are associated with numerous neurological disorders, yet the specific metabolic signaling pathways and brain regions involved in PPD remain unelucidated. METHODS: We performed behavioral test in the virgin and postpartum mice. We used mass spectrometry imaging (MSI) and targeted metabolomics analyses to investigate the metabolic alternation in the brain of GABAAR Delta-subunit-deficient (Gabrd-/-) postpartum mice, a specific preclinical animal model of PPD. Next, we performed mechanism studies including qPCR, Western blot, immunofluorescence staining, electron microscopy and primary astrocyte culture. In the specific knockdown and rescue experiments, we injected the adeno-associated virus into the central amygdala (CeA) of female mice. RESULTS: We identified that prostaglandin D2 (PGD2) downregulation in the CeA was the most outstanding alternation in PPD, and then validated that lipocalin-type prostaglandin D synthase (L-PGDS)/PGD2 downregulation plays a causal role in depressive behaviors derived from PPD in both wild-type and Gabrd-/- mice. Furthermore, we verified that L-PGDS/PGD2 signaling dysfunction-induced astrocytes atrophy is mediated by Src phosphorylation both in vitro and in vivo. LIMITATIONS: L-PGDS/PGD2 signaling dysfunction may be only responsible for the depressive behavior rather than maternal behaviors in the PPD, and it remains to be seen whether this mechanism is applicable to all depression types. CONCLUSION: Our study identified abnormalities in the L-PGDS/PGD2 signaling in the CeA, which inhibited Src phosphorylation and induced astrocyte atrophy, ultimately resulting in the development of PPD in mice.

Anesthetic Propofol Promotes Tumor Metastasis in Lungs via GABAA R-Dependent TRIM21 Modulation of Src Expression.

Generation of circulating tumor cells (CTCs), a key step in tumor metastasis, occurs during surgical tumor resection, often performed under general anesthesia. Propofol is the commonly used anesthetic, but its effects on CTCs and tumor metastasis remain largely unknown. Propofol effects are investigated in an experimental metastasis model by injecting tumor cells and, subsequently, low- or standard-dose propofol to nude mice through tail vein. Propofol- or vehicle-treated tumor cells are also injected to the mice. An in vitro tumor cell-vascular endothelial cell adhesion assay, immunofluorescence, and other methods are employed to assess how propofol affects tumor cell adhesion and extension. Propofol induces more lung tumor metastasis in mice than control. Mechanistically, propofol enhances tumor cell adhesion and extension through GABAA R to downregulate TRIM21 expression, leading to upregulation of Src, a protein associated with cell adhesion. These results demonstrate that propofol may promote tumor metastasis through GABAA R-TRIM21-Src mechanism.