Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling.
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 CB1 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.
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
Peng
P
Zhong
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
Wei
W
Wang
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
Bin
B
Pan
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
Xiaojie
X
Liu
1] Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA [2] Department of Geriatrics, Qi-Lu Hospital of Shandong University, Key Laboratory of Proteomics of Shandong Province, Shandong, China.
Zhen
Z
Zhang
The Skaggs Institute for Chemical Biology, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
Jonathan Z
JZ
Long
Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV, USA.
Han-ting
HT
Zhang
The Skaggs Institute for Chemical Biology, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
Benjamin F
BF
Cravatt
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
Qing-song
QS
Liu
D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000627:therapeutic use*; D000229:Dependovirus / Q000235:genetics; D003863:Depression / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005106:Exploratory Behavior / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005518:Food Preferences / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D010880:Piperidines / Q000627:therapeutic use*; D013315:Stress, Psychological / Q000150:complications*; D013395:Sucrose / Q000008:administration & dosage; D013550:Swimming; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D000928:Antidepressive Agents; D052117:Benzodioxoles; D004791:Enzyme Inhibitors; C534333:JZL 184; D010880:Piperidines; D013395:Sucrose; D058570:TOR Serine-Threonine Kinases; D008994:Monoacylglycerol Lipases