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At many central synapses, endocannabinoids released by postsynaptic cells inhibit neurotransmitter release by activating presynaptic cannabinoid receptors. The mechanisms underlying this important means of synaptic regulation are not fully understood. It has been shown at several synapses that endocannabinoids inhibit neurotransmitter release by reducing calcium influx into presynaptic terminals. One hypothesis maintains that endocannabinoids indirectly reduce calcium influx by modulating potassium channels and narrowing the presynaptic action potential. An alternative hypothesis is that endocannabinoids directly and selectively inhibit N-type calcium channels in presynaptic terminals. Here we test these hypotheses at the granule cell to Purkinje cell synapse in cerebellar brain slices. By monitoring optically the presynaptic calcium influx (Ca(influx)) and measuring the EPSC amplitudes, we found that cannabinoid-mediated inhibition arises solely from reduced presynaptic Ca(influx). Next we found that cannabinoid receptor activation does not affect the time course of presynaptic calcium entry, indicating that the reduced Ca(influx) reflects inhibition of presynaptic calcium channels. Finally, we assessed the classes of presynaptic calcium channels inhibited by cannabinoid receptor activation via peptide calcium channel antagonists. Previous studies established that N-type, P/Q-type, and R-type calcium channels are all present in granule cell presynaptic boutons. We found that cannabinoid activation reduced Ca(influx) through N-type, P/Q-type, and R-type calcium channels to 29, 60, and 55% of control, respectively. Thus, rather than narrowing the presynaptic action potential or exclusively modulating N-type calcium channels, CB1 receptor activation inhibits synaptic transmission by modulating all classes of calcium channels present in the presynaptic terminal of the granule cell to Purkinje cell synapse.

Endocannabinoids Inhibit Transmission at Granule Cell to Purkinje Cell Synapses by Modulating Three Types of Presynaptic Calcium Channels