背景:产后抑郁症(PPD)是一种严重的精神疾病,对产妇健康有显著的不利影响。大脑中的代谢异常与许多神经系统疾病有关,然而,PPD涉及的特定代谢信号通路和脑区仍未阐明.
方法:我们在初生和产后小鼠中进行了行为测试。我们使用质谱成像(MSI)和靶向代谢组学分析来研究GABAARDelta亚基缺陷(Gabrd-/-)产后小鼠大脑中的代谢变化,一种特定的PPD临床前动物模型。接下来,我们进行了机理研究,包括qPCR,蛋白质印迹,免疫荧光染色,电子显微镜和原代星形胶质细胞培养。在特定的击倒和救援实验中,我们将腺相关病毒注射到雌性小鼠的中央杏仁核(CeA)中。
结果:我们发现CeA中的前列腺素D2(PGD2)下调是PPD中最突出的变化,然后验证了脂质运载蛋白型前列腺素D合酶(L-PGDS)/PGD2下调在野生型和Gabrd-/-小鼠中PPD引起的抑郁行为中起因果作用。此外,我们在体内和体外证实了L-PGDS/PGD2信号传导功能障碍诱导的星形胶质细胞萎缩是由Src磷酸化介导的。
结论:L-PGDS/PGD2信号传导功能障碍可能仅是PPD中的抑郁行为而不是母体行为的原因,这种机制是否适用于所有抑郁症类型还有待观察。.
结论:我们的研究发现CeA中L-PGDS/PGD2信号异常,抑制Src磷酸化并诱导星形胶质细胞萎缩,最终导致小鼠PPD的发展。
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.
CONCLUSIONS: 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.
CONCLUSIONS: 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.