TY - JOUR T1 - Neuronal and astrocytic monoacylglycerol lipase limit the spread of endocannabinoid signaling in the cerebellum JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0048-16.2016 SP - ENEURO.0048-16.2016 AU - Yao Chen AU - Xiaojie Liu AU - Casey R. Vickstrom AU - Michelle J. Liu AU - Li Zhao AU - Andreu Viader AU - Benjamin F. Cravatt AU - Qing-song Liu Y1 - 2016/05/06 UR - http://www.eneuro.org/content/early/2016/05/06/ENEURO.0048-16.2016.abstract N2 - Endocannabinoids are diffusible lipophilic molecules that may spread to neighboring synapses. Monoacylglycerol lipase (MAGL) is the principal enzyme that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG). Using knockout mice in which MAGL is deleted globally or selectively in neurons and astrocytes, we investigated the extent to which neuronal and astrocytic MAGL limit the spread of 2-AG-mediated retrograde synaptic depression in cerebellar slices. A brief tetanic stimulation of parallel fibers in the molecular layer induced synaptically evoked suppression of excitation (SSE) in Purkinje cells, and both neuronal and astrocytic MAGL contribute to the termination of this form of endocannabinoid-mediated synaptic depression. The spread of SSE among Purkinje cells occurred only after global knockout of MAGL or pharmacological blockade of either MAGL or glutamate uptake, but no spread was detected following neuron- or astrocyte-specific deletion of MAGL. The spread of endocannabinoid signaling was also influenced by the spatial pattern of synaptic stimulation as it did not occur at spatially dispersed parallel fiber synapses induced by stimulating the granular layer. The tetanic stimulation of parallel fibers did not induce endocannabinoid-mediated synaptic suppression in Golgi cells even after disruption of MAGL and glutamate uptake, suggesting that heightened release of 2-AG by Purkinje cells does not spread the retrograde signal to parallel fibers that innervate Golgi cells. These results suggest that both neuronal and astrocytic MAGL limit the spatial diffusion of 2-AG and confer synapse-specificity of endocannabinoid signaling.Significance Statement: 2-Arachidonoylglycerol (2-AG) is an endogenous cannabinoid that depresses synaptic transmission through stimulation of CB1 receptors. Monoacylglycerol lipase (MAGL), the enzyme responsible for the majority of 2-AG degradation, is expressed by both neurons and astrocytes. We studied the extent to which neuronal and astrocytic MAGL contribute to termination of 2-AG signaling in the cerebellum. We show that 2-AG-mediated synaptic depression was prolonged in mutant mice that lack MAGL entirely or selectively in either neurons or astrocytes, and that total loss of MAGL causes diffusion of 2-AG to neighboring synapses. These results suggest that neurons and astrocytes collaborate to terminate 2-AG-mediated synaptic depression and limit the spread of 2-AG signaling. ER -