Monoacylglycerol Lipase Inhibition Blocks Chronic Stress-Induced Depressive-Like Behaviors via Activation of mTOR Signaling
Monoacylglycerol Lipase Inhibition Blocks Chronic Stress-Induced Depressive-Like Behaviors via Activation of mTOR Signaling
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DOI：
10.1038/npp.2014.24
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发表时间：
2014-01
影响因子：
7.6
通讯作者：
Peng Zhong;Wei Wang;B. Pan;Xiaojie Liu;Zhen Zhang;J. Long;Han-Ting Zhang;B. Cravatt;Qing-song L
中科院分区：
文献类型：
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作者：
Peng Zhong;Wei Wang;B. Pan;Xiaojie Liu;Zhen Zhang;J. Long;Han-Ting Zhang;B. Cravatt;Qing-song L
内源性大麻素（eCB）系统调节情绪，情感和压力应对，和失调的eCB系统是严重参与抑郁症的病理生理。eCB配体2-花生四烯酰甘油（2-AG）被单酰基甘油脂肪酶（MAGL）灭活。使用慢性不可预测的轻度应激（CUS）作为抑郁症的小鼠模型，我们研究了海马中的2-AG信号在抑郁样状态下是如何改变的，以及这种改变如何导致抑郁样行为。我们报告，CUS导致小鼠海马CA 1区锥体神经元的去极化诱导抑制（DSI）受损，MAGL抑制剂JZL 184挽救了2-AG介导的逆行性突触抑制的缺陷。CUS诱导抑郁样行为和减少哺乳动物雷帕霉素靶蛋白（mTOR）在海马中的激活，这些生化和行为异常通过长期JZL 184治疗得到改善。JZL 184的作用是通过大麻素CB 1受体介导的。用携带Cre重组酶的腺相关病毒（AAV）载体在mTORf/f小鼠海马中遗传缺失mTOR，重现了CUS诱导的抑郁样行为，并消除了慢性JZL 184治疗的抗抑郁样作用。我们的研究结果表明，CUS降低海马中的eCB-mTOR信号传导，导致抑郁样行为，而MAGL抑制剂JZL 184通过增强eCB-mTOR信号传导产生抗抑郁样作用。
The endocannabinoid (eCB) system regulates mood, emotion, and stress coping, and dysregulation of the eCB system is critically involved in pathophysiology of depression. The eCB ligand 2-arachidonoylglycerol (2-AG) is inactivated by monoacylglycerol lipase (MAGL). Using chronic unpredictable mild stress (CUS) as a mouse model of depression, we examined how 2-AG signaling in the hippocampus was altered in depressive-like states and how this alteration contributed to depressive-like behavior. We report that CUS led to impairment of depolarization-induced suppression of inhibition (DSI) in mouse hippocampal CA1 pyramidal neurons, and this deficiency in 2-AG-mediated retrograde synaptic depression was rescued by MAGL inhibitor JZL184. CUS induced depressive-like behaviors and decreased mammalian target of rapamycin (mTOR) activation in the hippocampus, and these biochemical and behavioral abnormalities were ameliorated by chronic JZL184 treatments. The effects of JZL184 were mediated by cannabinoid CB 1 receptors. Genetic deletion of mTOR with adeno-associated viral (AAV) vector carrying the Cre recombinase in the hippocampus of mTORf/f mice recapitulated depressive-like behaviors induced by CUS and abrogated the antidepressant-like effects of chronic JZL184 treatments. Our results suggest that CUS decreases eCB-mTOR signaling in the hippocampus, leading to depressive-like behaviors, whereas MAGL inhibitor JZL184 produces antidepressant-like effects through enhancement of eCB-mTOR signaling.