Retrograde modulation of synaptic transmission mediated by endogenous cannabinoids

Recent electrophysiological studies have clarified that endogenous cannabinoids (endocannabinoids) mediate retrograde signals from postsynaptic neurons to presynaptic terminals in the CNS. Endocannabinoids can be released from postsynaptic neurons following depolarization-induced elevation of intracellular Ca²⁺ concentration. The released endocannabinoids act retrogradely onto presynaptic cannabinoid CB1 receptors and suppress inhibitory or excitatory neurotransmitter release. This type of modulation has been termed depolarization-induced suppression of inhibition (DSI) or excitation (DSE). Endocannabinoid release and resultant retrograde suppression of transmitter release are also triggered by activation of group I metabotrophic glutamate receptors (mGluRs) or muscarinic acetylcholine receptors (mAChRs) in the postsynaptic neurons. This pathway can work independently of the depolarization-induced mechanism, because group I mGluR activation can produce endocannabinoids when the postsynaptic neuron is loaded with the fast Ca²⁺ buffer BAPTA. Nevertheless, evidence suggests that these two pathways for endocannabinoid production can work cooperatively in neurons. It is shown that DSI is enhanced significantly when group I mGluRs, or mAChRs is activated simultaneously by its specific agonists. This enhancement is much more prominent than what is expected from the simple summation of depolarization-induced and group I mGluR/mAChR-induced endocannabinoid release. Activation of group I mGluRs or mAChRs causes no significant change in depolarization-induced Ca²⁺ transients, indicating that the enhanced DSI does not result from the augmentation of Ca²⁺ influx. The CB1, group I mGluRs, mAChRs and voltage-gated Ca²⁺ channels are all expressed widely in the CNS. Thus, the endocannabinoid-mediated retrograde modulation is an important and widespread mechanism for the regulation of synaptic transmission in the CNS.