Genetic deletion of monoacylglycerol lipase alters endocannabinoid-mediated retrograde synaptic depression in the cerebellum

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.