Metabolic Interplay between Astrocytes and Neurons Regulates Endocannabinoid Action

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arachidonic Acids / genetics
  • Arachidonic Acids / metabolism*
  • Astrocytes / cytology
  • Astrocytes / metabolism*
  • Cell Communication / physiology*
  • Endocannabinoids / genetics
  • Endocannabinoids / metabolism*
  • Glycerides / genetics
  • Glycerides / metabolism*
  • Mice
  • Mice, Knockout
  • Monoacylglycerol Lipases / genetics
  • Monoacylglycerol Lipases / metabolism
  • Neurons / cytology
  • Neurons / metabolism*
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism

Substances

  • Arachidonic Acids
  • Endocannabinoids
  • Glycerides
  • Receptor, Cannabinoid, CB1
  • glyceryl 2-arachidonate
  • Monoacylglycerol Lipases