Cell Reports
Volume 12, Issue 5, 4 August 2015, Pages 798-808
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Article
Metabolic Interplay between Astrocytes and Neurons Regulates Endocannabinoid Action

https://doi.org/10.1016/j.celrep.2015.06.075Get rights and content
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open access

Highlights

  • Genetic mouse models reveal cellular specificity of 2-AG metabolism

  • Astrocytes and neurons collaborate to terminate endocannabinoid signaling

  • Coordinated astrocytic-neuronal metabolism protects against CB1R desensitization

  • Astrocytes couple 2-AG hydrolysis to neuroinflammatory prostaglandin production

Summary

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.

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).