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

Academic Article
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Overview

related to degree

  • Long, Jonathan, Ph.D. in Chemistry, Scripps Research 2007 - 2011

authors

  • Zhong, P.
  • Wang, W.
  • Pan, B.
  • Liu, X.
  • Zhang, Z.
  • Long, Jonathan
  • Zhang, H. T.
  • Cravatt, Benjamin
  • Liu, Q. S.

publication date

  • June 2014

journal

  • Neuropsychopharmacology  Journal

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 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.

subject areas

  • Animals
  • Antidepressive Agents
  • Benzodioxoles
  • Dependovirus
  • Depression
  • Disease Models, Animal
  • Enzyme Inhibitors
  • Exploratory Behavior
  • Feeding Behavior
  • Food Preferences
  • Hippocampus
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monoacylglycerol Lipases
  • Neurons
  • Piperidines
  • Stress, Psychological
  • Sucrose
  • Swimming
  • TOR Serine-Threonine Kinases
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Research

keywords

  • DSI
  • depression
  • endocannabinoid
  • hippocampus
  • mTOR
  • monoacylglycerol lipase
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Identity

PubMed Central ID

  • PMC4023150

International Standard Serial Number (ISSN)

  • 0893-133X

Digital Object Identifier (DOI)

  • 10.1038/npp.2014.24

PubMed ID

  • 24476943
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Additional Document Info

start page

  • 1763

end page

  • 1776

volume

  • 39

issue

  • 7

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