title: Metabolic Interplay between Astrocytes and Neurons Regulates Endocannabinoid Action.
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.
authors.affiliation: 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.
authors.forename: Andreu
authors.initials: A
authors.lastname: Viader
authors.affiliation: Abide Therapeutics, San Diego, CA 92121, USA.
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Blankman
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Liu
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Schlosburg
authors.affiliation: 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.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Joslyn
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Qing-Song
authors.initials: QS
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Tomarchio
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Sim-Selley
authors.affiliation: 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.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology*; D063388:Endocannabinoids / Q000235:genetics / Q000378:metabolism*; D005989:Glycerides / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D043884:Receptor, Cannabinoid, CB1; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases