title: Coordinated regulation of endocannabinoid-mediated retrograde synaptic suppression in the cerebellum by neuronal and astrocytic monoacylglycerol lipase.
abstract: The endocannabinoid 2-arachidonoylglycerol (2-AG) mediates retrograde synaptic depression including depolarization-induced suppression of excitation (DSE) and inhibition (DSI). 2-AG is degraded primarily by monoacylglycerol lipase (MAGL), which is expressed in neurons and astrocytes. Using knockout mice in which MAGL is deleted globally or selectively in neurons or astrocytes, we investigated the relative contribution of neuronal and astrocytic MAGL to the termination of DSE and DSI in Purkinje cells (PCs) in cerebellar slices. We report that neuronal MAGL plays a predominant role in terminating DSE at climbing fiber (CF) to PC synapses, while both neuronal and astrocytic MAGL significantly contributes to the termination of DSE at parallel fiber (PF) to PC synapses and DSI at putative Stellate cell to PC synapses. Thus, DSE and DSI at different synapses is not uniformly affected by global and cell type-specific knockout of MAGL. Additionally, MAGL global knockout, but not cell type-specific knockout, caused tonic activation and partial desensitization of the CB1receptor at PF-PC synapses. This tonic CB1activation is mediated by 2-AG since it was blocked by the diacylglycerol lipase inhibitor DO34. Together, these results suggest that both neuronal and astrocytic MAGL contribute to 2-AG clearance and prevent CB1receptor over-stimulation in the cerebellum.
authors: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226.
authors: Xiaojie
authors: X
authors: Liu
authors: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226.
authors: Yao
authors: Y
authors: Chen
authors: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226.
authors: Casey R
authors: CR
authors: Vickstrom
authors: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226.
authors: Yan
authors: Y
authors: Li
authors: The Skaggs Institute for Chemical Biology, Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors: Andreu
authors: A
authors: Viader
authors: The Skaggs Institute for Chemical Biology, Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors: Benjamin F
authors: BF
authors: Cravatt
authors: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226.
authors: Qing-Song
authors: QS
authors: Liu
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001253:Astrocytes / Q000502:physiology; D052117:Benzodioxoles / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005989:Glycerides / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D011689:Purkinje Cells / Q000502:physiology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
chemical_list: D001095:Arachidonic Acids; D052117:Benzodioxoles; D048588:Benzoxazines; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; C534333:JZL 184; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases