The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase alpha mediates retrograde suppression of synaptic transmission.
Endocannabinoids are released from postsynaptic neurons and cause retrograde suppression of synaptic transmission. Anandamide and 2-arachidonoylglycerol (2-AG) are regarded as two major endocannabinoids. To determine to what extent 2-AG contributes to retrograde signaling, we generated and analyzed mutant mice lacking either of the two 2-AG synthesizing enzymes diacylglycerol lipase alpha (DGLalpha) and beta (DGLbeta). We found that endocannabinoid-mediated retrograde synaptic suppression was totally absent in the cerebellum, hippocampus, and striatum of DGLalpha knockout mice, whereas the retrograde suppression was intact in DGLbeta knockout brains. The basal 2-AG content was markedly reduced and stimulus-induced elevation of 2-AG was absent in DGLalpha knockout brains, whereas the 2-AG content was normal in DGLbeta knockout brains. Morphology of the brain and expression of molecules required for 2-AG production other than DGLs were normal in the two knockout mice. We conclude that 2-AG produced by DGLalpha, but not by DGLbeta, mediates retrograde suppression at central synapses.
Department of Neurophysiology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Asami
A
Tanimura
Maya
M
Yamazaki
Yuki
Y
Hashimotodani
Motokazu
M
Uchigashima
Shinya
S
Kawata
Manabu
M
Abe
Yoshihiro
Y
Kita
Kouichi
K
Hashimoto
Takao
T
Shimizu
Masahiko
M
Watanabe
Kenji
K
Sakimura
Masanobu
M
Kano
D000818:Animals; D000831:Animals, Newborn; D001095:Arachidonic Acids / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004558:Electric Stimulation / Q000379:methods; D063388:Endocannabinoids; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D005990:Glycerol / Q000031:analogs & derivatives* / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D008071:Lipoprotein Lipase / Q000145:classification / Q000172:deficiency / Q000378:metabolism*; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D018709:Statistics, Nonparametric; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D001095:Arachidonic Acids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D008734:Methoxyhydroxyphenylglycol; D011189:Potassium Chloride; D008071:Lipoprotein Lipase; D005990:Glycerol; D002118:Calcium; C010117:3,4-dihydroxyphenylglycol; C078814:anandamide