RT Journal Article
SR Electronic
T1 Endocannabinoids Inhibit Transmission at Granule Cell to Purkinje Cell Synapses by Modulating Three Types of Presynaptic Calcium Channels
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 5623
OP 5631
DO 10.1523/JNEUROSCI.0918-04.2004
VO 24
IS 24
A1 Solange P. Brown
A1 Patrick K. Safo
A1 Wade G. Regehr
YR 2004
UL http://www.jneurosci.org/content/24/24/5623.abstract
AB 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 (Cainflux) and measuring the EPSC amplitudes, we found that cannabinoid-mediated inhibition arises solely from reduced presynaptic Cainflux. Next we found that cannabinoid receptor activation does not affect the time course of presynaptic calcium entry, indicating that the reduced Cainflux 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 Cainflux 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.