title: Neuronal and Astrocytic Monoacylglycerol Lipase Limit the Spread of Endocannabinoid Signaling in the Cerebellum.
abstract: Endocannabinoids are diffusible lipophilic molecules that may spread to neighboring synapses. Monoacylglycerol lipase (MAGL) is the principal enzyme that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG). Using knock-out mice in which MAGL is deleted globally or selectively in neurons and astrocytes, we investigated the extent to which neuronal and astrocytic MAGL limit the spread of 2-AG-mediated retrograde synaptic depression in cerebellar slices. A brief tetanic stimulation of parallel fibers in the molecular layer induced synaptically evoked suppression of excitation (SSE) in Purkinje cells, and both neuronal and astrocytic MAGL contribute to the termination of this form of endocannabinoid-mediated synaptic depression. The spread of SSE among Purkinje cells occurred only after global knock-out of MAGL or pharmacological blockade of either MAGL or glutamate uptake, but no spread was detected following neuron- or astrocyte-specific deletion of MAGL. The spread of endocannabinoid signaling was also influenced by the spatial pattern of synaptic stimulation, because it did not occur at spatially dispersed parallel fiber synapses induced by stimulating the granular layer. The tetanic stimulation of parallel fibers did not induce endocannabinoid-mediated synaptic suppression in Golgi cells even after disruption of MAGL and glutamate uptake, suggesting that heightened release of 2-AG by Purkinje cells does not spread the retrograde signal to parallel fibers that innervate Golgi cells. These results suggest that both neuronal and astrocytic MAGL limit the spatial diffusion of 2-AG and confer synapse-specificity of endocannabinoid signaling.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin , Milwaukee, Wisconsin 53226.
authors.forename: Xiaojie
authors.identifier: 0000-0001-9843-1674
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin , Milwaukee, Wisconsin 53226.
authors.forename: Casey R
authors.identifier: 0000-0003-0536-1211
authors.initials: CR
authors.lastname: Vickstrom
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin , Milwaukee, Wisconsin 53226.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Liu
authors.affiliation: Department of Exercise Physiology, Beijing Sport University , Beijing 100084, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute , La Jolla, California 92037.
authors.forename: Andreu
authors.initials: A
authors.lastname: Viader
authors.affiliation: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute , La Jolla, California 92037.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin , Milwaukee, Wisconsin 53226.
authors.forename: Qing-Song
authors.identifier: 0000-0003-1858-1504
authors.initials: QS
authors.lastname: Liu
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology*; D063388:Endocannabinoids / Q000378:metabolism* / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D005989:Glycerides / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D018408:Patch-Clamp Techniques; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D046509:Tissue Culture Techniques
chemical_list: D027322:Amino Acid Transport System X-AG; D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D005989:Glycerides; D018698:Glutamic Acid; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases
keywords: 2-arachidonoylglycerol; Purkinje cells; astrocyte; cerebellum; endocannabinoid; monoacylglycerol lipase