Stimulation of endocannabinoid formation in brain slice cultures through activation of group I metabotropic glutamate receptors.
Activation of group I metabotropic glutamate (mGlu) receptors drives the endocannabinoid system to cause both short- and long-term changes of synaptic strength in the striatum, hippocampus, and other brain areas. Although there is strong electrophysiological evidence for a role of endocannabinoid release in mGlu receptor-dependent plasticity, the identity of the endocannabinoid transmitter mediating this phenomenon remains undefined. In this study, we show that activation of group I mGlu receptors triggers the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG), but not anandamide, in primary cultures of corticostriatal and hippocampal slices prepared from early postnatal rat brain. Pharmacological studies suggest that 2-AG biosynthesis is initiated by activation of mGlu5 receptors, is catalyzed by phospholipase C (PLC) and 1,2-diacylglycerol lipase (DGL) activities, and is dependent on intracellular Ca2+ ions. Realtime polymerase chain reaction and immunostaining analyses indicate that DGL-beta is the predominant DGL isoform expressed in corticostriatal and hippocampal slices and that this enzyme is highly expressed in striatal neurons, where it is colocalized with PLC-beta1. The results suggest that 2-AG is a primary endocannabinoid mediator of mGlu receptor-dependent neuronal plasticity.
Jung
Kwang-Mook
KM
Department of Pharmacology, 3101 Gillespie NRF, University of California, Irvine, CA 92697-4625. piomelli@uci.edu.
Mangieri
Regina
R
Stapleton
Christopher
C
Kim
Janet
J
Fegley
Darren
D
Wallace
Matthew
M
Mackie
Ken
K
Piomelli
Daniele
D
D000595:Amino Acid Sequence; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000096:biosynthesis*; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000502:physiology; D008969:Molecular Sequence Data; D009473:Neuronal Plasticity; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D010738:Type C Phospholipases / Q000502:physiology
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C094503:glyceryl 2-arachidonate; D008071:Lipoprotein Lipase; D010738:Type C Phospholipases; D002118:Calcium