Document Type

Article

Original Publication Date

2015

Journal/Book/Conference Title

Cell Reports

Volume

12

Issue

5

DOI of Original Publication

10.1016/j.celrep.2015.06.075

Comments

Originally published at http://dx.doi.org/10.1016/j.celrep.2015.06.075

Date of Submission

November 2015

Abstract

The endocannabinoid 2-arachidonoylglycerol (2-AG) is a retrograde lipid messenger that modulates synaptic function, neurophysiology, and behavior. 2-AG signaling is terminated by enzymatic hydrolysis—a reaction that is principally performed by monoacylglycerol lipase (MAGL). MAGL is broadly expressed throughout the nervous system, and the contributions of different brain cell types to the regulation of 2-AG activityin vivo remain poorly understood. Here, we genetically dissect the cellular anatomy of MAGL-mediated 2-AG metabolism in the brain and show that neurons and astrocytescoordinately regulate 2-AG content and endocannabinoid-dependent forms of synaptic plasticity and behavior. We also find that astrocytic MAGL is mainly responsible for converting 2-AG to neuroinflammatory prostaglandins via a mechanism that may involve transcellular shuttling of lipid substrates. Astrocytic-neuronal interplay thus provides distributed oversight of 2-AG metabolism and function and, through doing so, protects the nervous system from excessive CB1 receptor activation and promotes endocannabinoid crosstalk with other lipid transmitter systems.

Rights

Copyright © 2015 The Authors. Published by Elsevier Inc.

Is Part Of

VCU Pharmacology and Toxicology Publications

mmc1.pdf (7993 kB)
Document S1. Supplemental Experimental Procedures, Figures S1–S5, and Table S1.

mmc2.pdf (11090 kB)
Document S2. Article plus Supplemental Information.

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