Miniature Synaptic Events Elicited by Presynaptic Ca2+ Rise Are Selectively Suppressed by Cannabinoid Receptor Activation in Cerebellar Purkinje Cells

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Abstract
Activation of cannabinoid receptors suppresses neurotransmitter release in various brain regions. In cerebellar Purkinje cells (PCs), cannabinoid agonists suppress both EPSC and IPSC evoked by stimulating the corresponding inputs. However, cannabinoid agonists suppress miniature IPSC (mIPSC) but not miniature EPSC (mEPSC) at normal external Ca2+concentration ([Ca2+]o). Therefore, cannabinoid agonists are thought to suppress release machinery for IPSCs but not that for EPSCs. Here we investigated the possible cause of this difference and found that cannabinoid agonists selectively suppressed Ca2+-enhanced miniature events. A cannabinoid agonist, WIN55,212-2 (5 μm), did not affect mEPSC frequency with 2 mmextracellular Ca2+(Ca2+o). However, WIN55,212-2 became effective when mEPSC frequency was enhanced by elevation of presynaptic Ca2+level by perfusion with 5 mmCa2+oor bath application of A23187, a Ca2+ionophore. In contrast, WIN55,212-2 suppressed mIPSC frequency with 2 mmCa2+o, but it became ineffective when the presynaptic Ca2+level was lowered by perfusion with a Ca2+-free solution containing BAPTA-AM. Experiments with systematic [Ca2+]ochanges revealed that mIPSC but not mEPSC regularly involved events elicited by presynaptic Ca2+rise with 2 mmCa2+o. Importantly, Ca2+-enhancement of mEPSC and mIPSC was not attributable to activation of voltage-dependent Ca2+channels. Activation of GABABreceptor or group III metabotropic glutamate receptor, which couple to Gi/o-protein, also preferentially suppressed Ca2+-enhanced miniature events in PCs. These results suggest that the occurrence of Ca2+-enhanced miniature events at normal [Ca2+]odetermines the sensitivity to the presynaptic depression mediated by cannabinoid receptors and other Gi/o-coupled receptors in PCs.

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