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, I analyzed mutant mice lacking either of the two 2-AG synthesizing enzymes diacylglycerol lipase α (DGLα) and β (DGLβ). Endocannabinoid-mediated retrograde synaptic suppression was totally absent in the cerebellum, hippocampus and striatum of DGLα knockout mice, whereas the retrograde suppression was intact in DGLβ knockout brains. These results clearly indicate that 2-AG produced by DGLα, not by DGLβ, mediates retrograde synaptic suppression. To elucidate how 2-AG signaling is terminated after inducing retrograde synaptic suppression, I examined the cerebellum of mice lacking the 2-AG hydrolyzing enzyme monoacylglycerol lipase (MGL) or mice with cerebellar granule cell (GC)-specific deletion of MGL. In wild-type cerebellum, MGL was expressed richly in terminals of parallel fibers (PFs), the axons of GCs, and weakly in Bergman glia (BG), but was absent in climbing fiber (CF) terminals and GABAergic 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 CF-PC synapses in GC-specific MGL knockout mice. Virus-mediated expression of MGL into 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. These results indicate that 2-AG is degraded in a synapse type-independent manner by MGL present in PFs and BG.
発行年
2013-03-25
学位名
博士(医学)
学位
doctoral
学位分野
Medical Science(医学)
学位授与機関
University of Tokyo (東京大学)
研究科・専攻
Department of Functional Biology, Graduate School of Medicine(医学系研究科機能生物学専攻)
学位授与年月日
2013-03-25
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Synaptic modulation mediated by the endocannabinoid 2-arachidonoylglycerol in the central nervous system
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