Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Department of Anesthesiology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 201204, China.
Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
J Affect Disord. 2024 Aug 15;359:241-252. doi: 10.1016/j.jad.2024.05.083. Epub 2024 May 18.
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.
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 GABAR 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.
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.
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.
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.
产后抑郁症（PPD）是一种严重的精神疾病，对产妇健康有重大的不利影响。大脑中的代谢异常与许多神经疾病有关，但与 PPD 相关的特定代谢信号通路和大脑区域仍未阐明。
我们对处女和产后的小鼠进行了行为测试。我们使用质谱成像（MSI）和靶向代谢组学分析来研究 GABAR Delta 亚基缺失（Gabrd）产后小鼠（一种特定的产后抑郁症的临床前动物模型）大脑中的代谢改变。接下来，我们进行了机制研究，包括 qPCR、Western blot、免疫荧光染色、电子显微镜和原代星形胶质细胞培养。在特定的敲低和挽救实验中，我们将腺相关病毒注入雌性小鼠的中央杏仁核（CeA）。
我们发现 CeA 中前列腺素 D2（PGD2）的下调是 PPD 中最显著的改变，然后验证了 L-PGDS/PGD2 的下调在野生型和 Gabrd 小鼠中都在产后抑郁症衍生的抑郁行为中起着因果作用。此外，我们验证了 L-PGDS/PGD2 信号功能障碍诱导的星形胶质细胞萎缩是由Src 磷酸化介导的，无论是在体外还是体内。
L-PGDS/PGD2 信号功能障碍可能仅负责 PPD 中的抑郁行为而不是母性行为，而且这种机制是否适用于所有类型的抑郁症仍有待观察。
我们的研究确定了 CeA 中 L-PGDS/PGD2 信号的异常，该异常抑制了 Src 磷酸化并诱导了星形胶质细胞萎缩，最终导致了小鼠 PPD 的发展。
