Major depressive disorder (MDD) is a severe disease of unknown pathogenesis that will affect ∼10% of people during their lifetime. Therapy for MDD requires prolonged treatment and often fails, predicating a need for novel treatment strategies. Here, we report increased ceramide levels in the blood plasma of MDD patients and in murine stress-induced models of MDD. These blood plasma ceramide levels correlated with the severity of MDD in human patients and were independent of age, sex, or body mass index. In addition, intravenous injection of anti-ceramide antibodies or neutral ceramidase rapidly abrogated stress-induced MDD, and intravenous injection of blood plasma from mice with MDD induced depression-like behavior in untreated mice, which was abrogated by ex vivo preincubation of the plasma with anti-ceramide antibodies or ceramidase. Mechanistically, we demonstrate that ceramide accumulated in endothelial cells of the hippocampus of stressed mice, evidenced by the quantitative measurement of ceramide in purified hippocampus endothelial cells. We found ceramide inhibited the activity of phospholipase D (PLD) in endothelial cells in vitro and in the hippocampus in vivo and thereby decreased phosphatidic acid in the hippocampus. Finally, we show intravenous injection of PLD or phosphatidic acid abrogated MDD, indicating the significance of this pathway in MDD pathogenesis. Our data indicate that ceramide controls PLD activity and phosphatidic acid formation in hippocampal endothelial cells and thereby mediates MDD. We propose that neutralization of plasma ceramide could represent a rapid-acting targeted treatment for MDD.

重度抑郁症 (MDD) 是一种发病机制不明的严重疾病，会在其一生中影响约 10% 的人。MDD 的治疗需要长时间的治疗并且经常失败，这预示着需要新的治疗策略。在这里，我们报告了 MDD 患者血浆和小鼠应激诱导的 MDD 模型中神经酰胺水平的升高。这些血浆神经酰胺水平与人类患者 MDD 的严重程度相关，并且与年龄、性别或体重指数无关。此外，静脉注射抗神经酰胺抗体或中性神经酰胺酶可迅速消除应激诱导的 MDD，静脉注射患有 MDD 的小鼠的血浆可诱导未经治疗的小鼠出现抑郁样行为，而这种行为已被体外消除。用抗神经酰胺抗体或神经酰胺酶预孵育血浆。从机制上讲，我们证明神经酰胺在应激小鼠的海马内皮细胞中积累，这可以通过纯化海马内皮细胞中神经酰胺的定量测量来证明。我们发现神经酰胺抑制体外内皮细胞和体内海马中磷脂酶 D (PLD) 的活性从而减少海马中的磷脂酸。最后，我们显示静脉注射 PLD 或磷脂酸消除了 MDD，表明该途径在 MDD 发病机制中的重要性。我们的数据表明神经酰胺控制海马内皮细胞中的 PLD 活性和磷脂酸形成，从而介导 MDD。我们建议中和血浆神经酰胺可以代表 MDD 的快速靶向治疗。