How do endocannabinoids send a message backwards across a synapse? · Grey Matter

When a neuron is strongly depolarised, the calcium that enters it (or certain metabotropic receptors) activates enzymes in its membrane that make 2-AG, a lipid that is not stored but made on demand.

How do endocannabinoids send a message backwards across a synapse?

When a neuron is strongly depolarised, the calcium that enters it (or certain metabotropic receptors) activates enzymes in its membrane that make 2-AG, a lipid that is not stored but made on demand. 2-AG diffuses out of the cell, back across the cleft, and binds CB1 receptors on the presynaptic terminals that contact it. CB1 receptors inhibit the terminal's calcium channels, so the probability of release falls for tens of seconds, and with repeated activation the depression can become long-lasting. In depolarisation-induced suppression of inhibition, a pyramidal cell that fires hard uses this route to turn down the GABA arriving onto itself.