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Cell Rep. 2015 Aug 4;12(5):798-808. doi: 10.1016/j.celrep.2015.06.075. Epub 2015 Jul 23.

Metabolic Interplay between Astrocytes and Neurons Regulates Endocannabinoid Action.

Author information

1
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
2
Abide Therapeutics, San Diego, CA 92121, USA.
3
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
4
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA.
5
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
6
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: cravatt@scripps.edu.

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 activity in 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 astrocytes coordinately 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.

PMID:
26212325
PMCID:
PMC4526356
DOI:
10.1016/j.celrep.2015.06.075
[Indexed for MEDLINE]
Free PMC Article

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