Synapse type-independent degradation of the endocannabinoid 2-arachidonoylglycerol after retrograde synaptic suppression.
The endocannabinoid 2-arachidonoylglycerol (2-AG) mediates retrograde synaptic suppression. Although the mechanisms of 2-AG production are well characterized, how 2-AG is degraded is less clearly understood. Here we found that expression of the 2-AG hydrolyzing enzyme monoacylglycerol lipase (MGL) was highly heterogeneous in the cerebellum, being rich within parallel fiber (PF) terminals, weak in Bergman glia (BG), and absent in other synaptic terminals. Despite this highly selective MGL expression pattern, 2-AG-mediated retrograde suppression was significantly prolonged at not only PF-Purkinje cell (PC) synapses but also climbing fiber-PC synapses in granule cell-specific MGL knockout (MGL-KO) mice whose cerebellar MGL expression was confined to the BG. Virus-mediated expression of MGL into the BG of global MGL-KO mice significantly shortened 2-AG-mediated retrograde suppression at PF-PC synapses. Furthermore, contribution of MGL to termination of 2-AG signaling depended on the distance from MGL-rich PFs to inhibitory synaptic terminals. Thus, 2-AG is degraded in a synapse-type independent manner by MGL present in PFs and the BG. The results of the present study strongly suggest that MGL regulates 2-AG signaling rather broadly within a certain range of neural tissue, although MGL expression is heterogeneous and limited to a subset of nerve terminals and astrocytes.
Department of Neurophysiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Asami
A
Tanimura
Motokazu
M
Uchigashima
Maya
M
Yamazaki
Naofumi
N
Uesaka
Takayasu
T
Mikuni
Manabu
M
Abe
Kouichi
K
Hashimoto
Masahiko
M
Watanabe
Kenji
K
Sakimura
Masanobu
M
Kano
D000704:Analysis of Variance; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D063388:Endocannabinoids; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005989:Glycerides / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D016133:Polymerase Chain Reaction; D059748:Proteolysis; D011689:Purkinje Cells / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D017931:DNA Primers; D063388:Endocannabinoids; D005989:Glycerides; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; D002118:Calcium