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Genetic deletion of monoacylglycerol lipase alters endocannabinoid-mediated retrograde synaptic depression in the cerebellum. J Physiol 2011 Oct 15;589(Pt 20):4847-55

Date

09/14/2011

Pubmed ID

21911610

Pubmed Central ID

PMC3224879

DOI

10.1113/jphysiol.2011.215509

Scopus ID

2-s2.0-80054113152 (requires institutional sign-in at Scopus site)   55 Citations

Abstract

The endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) is hydrolysed primarily by monoacylglycerol lipase (MAGL). Here, we investigated whether eCB-mediated retrograde synaptic depression in cerebellar slices was altered in MAGL knockout (MAGL(-/-)) mice. Depolarization-induced suppression of excitation (DSE) and metabotropic glutamate receptor (mGluR1)-mediated synaptic depression are mediated by 2-AG-induced activation of CB(1) receptors. We show that genetic deletion of MAGL prolonged DSE at parallel fibre (PF) or climbing fibre (CF) to Purkinje cell (PC) synapses. Likewise, mGluR1-mediated synaptic depression, induced either by high-frequency stimulation of PF or mGluR1 agonist DHPG, was prolonged in MAGL(-/-) mice. About 15% of 2-AG in the brain is hydrolysed by serine hydrolase α-β-hydrolase domain 6 and 12 (ABHD6 and ABHD12). However, the selective ABHD6 inhibitor WWL123 had no significant effect on cerebellar DSE in MAGL(+/+) and (-/-) mice. The CB(1) receptor antagonist SR141716 significantly increased the amplitude of basal excitatory postsynaptic currents (EPSCs) in MAGL(-/-) mice but not in MAGL(+/+) mice. Conversely, the CB(1) agonist WIN55212 induced less depression of basal EPSCs in MAGL(-/-) mice than in MAGL(+/+) mice. These results provide genetic evidence that inactivation of 2-AG by MAGL determines the time course of eCB-mediated retrograde synaptic depression and that genetic deletion of MAGL causes tonic activation and consequential desensitization of CB(1) receptors.

Author List

Zhong P, Pan B, Gao XP, Blankman JL, Cravatt BF, Liu QS

Author

Qing-song Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Arachidonic Acids
Cannabinoid Receptor Modulators
Cerebellum
Endocannabinoids
Female
Gene Deletion
Glycerides
In Vitro Techniques
Male
Mice
Mice, Knockout
Monoacylglycerol Lipases
Patch-Clamp Techniques
Purkinje Cells
Receptor, Cannabinoid, CB1
Synaptic Transmission