Cannabinoid receptor modulation of synapses received by cerebellar purkinje cells

The high density of cannabinoid receptors in the cerebellum and the degrada tion of motor coordination produced by cannabinoid intoxication suggest tha t synaptic transmission in the cerebellum may be strongly regulated by cann abinoid receptors. Therefore the effects of exogenous cannabinoids on synap ses received by Purkinje cells were investigated in rat cerebellar slices. Parallel fiber-evoked (PF) excitatory postsynaptic currents (EPSCs) were st rongly inhibited by bath application of the cannabinoid receptor agonist WI N 55212-2 (5 mu M, 12% of baseline EPSC amplitude). This effect was complet ely blocked by the cannabinoid CB1 receptor antagonist Se 141716. It is unl ikely that this was the result of alterations in axonal excitability becaus e fiber volley velocity and kinetics were unchanged and a cannabinoid-induc ed decrease in fiber volley amplitude was very minor (93% of baseline). WIN 55212-2 had no effect on the amplitude or frequency of spontaneously occur ring miniature EPSCs (mEPSCs), suggesting that the effect of CB1 receptor a ctivation on PF EPSCs was presynaptically expressed, but giving no evidence for modulation of release processes after Ca2+ influx. EPSCs evoked by cli mbing fiber (CF) stimulation were less powerfully attenuated by WIN 55212-2 (5 mu M, 74% of baseline). Large, action potential-dependent, spontaneousl y occurring inhibitory postsynaptic currents (sIPSCs) were either severely reduced in amplitude (<25% of baseline) or eliminated. Miniature IPSCs (mIP SCs) were reduced in frequency (52% of baseline) but not in amplitude, demo nstrating suppression of presynaptic vesicle release processes after Ca2+ i nflux and suggesting an absence of postsynaptic modulation. The decrease in mIPSC frequency was not large enough to account for the decrease in sIPSC amplitude, suggesting that presynaptic voltage-gated channel modulation was also involved. Thus, while CBI receptor activation reduced neurotransmitte r release at all major classes of Purkinje cell synapses, this was not acco mplished by a single molecular mechanism. At excitatory synapses, cannabino id suppression of neurotransmitter release was mediated by modulation of vo ltage-gated channels in the presynaptic axon terminal. At inhibitory synaps es, in addition to modulation of presynaptic voltage-gated channels, suppre ssion of the downstream vesicle release machinery also played a large role.