Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals

Endogenous cannabinoids are considered to function as diffusible and short- lived modulators that may transmit signals retrogradely from postsynaptic t o presynaptic neurons. To evaluate this possibility, we have made a paired whole-cell recording from cultured hippocampal neurons with inhibitory syna ptic connections. In about 60% of pairs, a cannabinoid agonist greatly redu ced the release of the inhibitory neurotransmitter GABA from presynaptic te rminals. In most of such pairs but not in those insensitive to the agonist, depolarization of postsynaptic neurons and the resultant elevation of intr acellular Ca2+ concentration caused transient suppression of inhibitory syn aptic currents, which is mainly due to reduction of GABA release. This depo larization-induced suppression was completely blocked by selective cannabin oid antagonists. Our results reveal that endogenous cannabinoids mediate re trograde signals from depolarized postsynaptic neurons to presynaptic termi nals to cause the reduction of transmitter release.