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PMID: 16973696 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Depolarization-induced retrograde synaptic inhibition in the mouse cerebellar cortex is mediated by 2-arachidonoylglycerol.

The Journal of physiology ·Vol. 577 ·No. Pt 1 ·2006-11-15 ·Pages 263-80

Szabo B, Urbanski MJ, Bisogno T, Di Marzo V, Mendiguren A, Baer WU, Freiman I

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.

MeSH Terms
Animals Arachidonic Acids/metabolism Cells, Cultured Cerebellar Cortex/physiology Endocannabinoids Glycerides/metabolism Interneurons/physiology Membrane Potentials/physiology Mice Neural Inhibition/physiology Neurotransmitter Agents/metabolism Polyunsaturated Alkamides/metabolism Purkinje Cells/physiology Synaptic Transmission/physiology
Chemicals
Arachidonic Acids Endocannabinoids Glycerides Neurotransmitter Agents Polyunsaturated Alkamides glyceryl 2-arachidonate anandamide
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Szabo Bela
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität; Albertstrasse 25, D-79104 Freiburg im Breisgau, Germany. [email protected]
Urbanski Michal J
Bisogno Tiziana
Di Marzo Vincenzo
Mendiguren Aitziber
Baer Wolfram U
Freiman Ilka
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Article Info
Journal
The Journal of physiology
Abbr.
J Physiol
ISSN
0022-3751
DOI
10.1113/jphysiol.2006.119362
Email
[email protected]
Published
2006-11-15
Epub
2006-00-14
Pages
263-80
Language
English
Region
England
NLM ID
0266262
PMCID
PMC2000676
Subset
IM
External Links
PubMed source DOI: 10.1113/jphysiol.2006.119362 PMC Full Text View journal details
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