The acid sphingomyelinase/ceramide hypothesis of major depression

重度抑郁症是一种严重的、经常危及生命的情绪障碍。然而，导致重度抑郁症的分子机制尚不清楚。先前，我们发现重度抑郁症患者的酸性鞘磷脂酶（ASM）活性增加，这与抗抑郁药物对ASM的功能抑制一致。在第一个资助期内产生的数据表明，阿米替林和氟西汀抑制应激和休息小鼠海马中的ASM，导致海马神经酰胺减少，神经发生和行为影响增加，这些事件在接受这些抗抑郁药物的ASM缺陷小鼠中都不存在。1)阿米替林和氟西汀用于抗抑郁治疗的浓度对ASM有功能抑制作用。在小鼠模型中，我们现在将确定抗抑郁药物和电痉挛刺激的神经生物学和行为效应是否通过抑制ASM介导；2)在细胞培养模型中，确定ASM是否参与突触传递的相关过程；3)在人类患者中，研究ASM作为诊断标志物的作用。

Major depression is a severe and often life-threatening mood disorder. The molecular mechanisms resulting in major depression are, however, unknown. Previously, we found increased activity of the acid sphingomyelinase (ASM) in patients suffering from major depression, consistent with the finding of the functional inhibition of the ASM by antidepressant drugs. Data generated during the first funding period demonstrate that amitriptyline and fluoxetine inhibit the ASM in the hippocampus of stressed and resting mice, resulting in reduction of hippocampal ceramide, increased neurogenesis and behavioural effects, events that were all absent in ASM-deficient mice receiving these antidepressant drugs. 1) Amitriptyline and fluoxetine functionally inhibit ASM in concentrations used for antidepressant therapy. In mouse models, we will now determine whether or not the neurobiological and behavioural effects of antidepressive drugs and electroconvulsive stimulation are mediated by inhibition of the ASM; 2) in cell culture models, determine whether or not ASM is involved in processes relevant for synaptic transmission; 3) in human patients, study the role of ASM as a diagnostic marker.