Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling

Peng Zhong, Wei Wang, Bin Pan, Xiaojie Liu, Zhen Zhang, Jonathan Z. Long, Han Ting Zhang, Benjamin F. Cravatt, Qing Song Liu

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1763-1776
Number of pages14
JournalNeuropsychopharmacology
Volume39
Issue number7
DOIs
StatePublished - Jun 2014
Externally publishedYes

Keywords

  • depression
  • DSI
  • Endocannabinoid
  • hippocampus
  • monoacylglycerol lipase
  • mTOR

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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