title: Depolarization-induced retrograde synaptic inhibition in the mouse cerebellar cortex is mediated by 2-arachidonoylglycerol.
abstract: Endocannabinoids acting on CB(1) cannabinoid receptors are involved in short- and long-term depression of synaptic transmission. The aim of the present study was to determine which endocannabinoid, anandamide or 2-arachidonoylglycerol (2-AG), is involved in depolarization-induced suppression of inhibition (DSI) in the cerebellar cortex, which is the most widely studied form of short-term depression. Depolarization of Purkinje cells in the mouse cerebellum led to an increase in intracellular calcium concentration and to suppression of the inhibitory input to these neurons (i.e. DSI occurred). Orlistat and RHC80267, two blockers of sn-1-diacylglycerol lipase, the enzyme catalysing 2-AG formation, abolished DSI by acting downstream of calcium influx. In contrast, DSI occurred also in the presence of a phospholipase C inhibitor. Intact operation of the calcium-dependent messengers calmodulin and Ca(2+)-calmodulin-dependent protein kinase II were necessary for DSI. DSI was potentiated by an inhibitor of the main 2-AG-degrading enzyme, monoacylglycerol lipase. Interference with the anandamide metabolizing enzyme, fatty acid amide hydrolase, did not modify DSI. Thus, three kinds of observations identified 2-AG as the endocannabinoid involved in DSI in the mouse cerebellum: DSI was abolished by diacylglycerol lipase inhibitors; DSI was potentiated by a monoglyceride lipase inhibitor; and DSI was not changed by an inhibitor of fatty acid amide hydrolase. Further experiments indicated that 2-AG is the endocannabinoid mediating short-term retrograde signalling also at other synapses: orlistat abolished DSI in the rat cerebellum, DSI in the mouse substantia nigra pars reticulata and depolarization-induced suppression of excitation in the mouse cerebellum.
authors.affiliation: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität; Albertstrasse 25, D-79104 Freiburg im Breisgau, Germany. szabo@pharmakol.uni-freiburg.de
authors.forename: Bela
authors.initials: B
authors.lastname: Szabo
authors.forename: Michal J
authors.initials: MJ
authors.lastname: Urbanski
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bisogno
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Aitziber
authors.initials: A
authors.lastname: Mendiguren
authors.forename: Wolfram U
authors.initials: WU
authors.lastname: Baer
authors.forename: Ilka
authors.initials: I
authors.lastname: Freiman
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000502:physiology*; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism*; D007395:Interneurons / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology*; D051379:Mice; D009433:Neural Inhibition / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011689:Purkinje Cells / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D018377:Neurotransmitter Agents; D053284:Polyunsaturated Alkamides; C094503:glyceryl 2-arachidonate; C078814:anandamide