Endocannabinoids · Grey Matter

Endocannabinoids are lipid messengers that a neuron makes on demand when it is strongly activated and sends backwards across its synapses, telling the terminals that feed it to release less; they are the brain's own version of the molecules that cannabis mimics.

Endocannabinoids. Endocannabinoids are lipid messengers that a neuron makes on demand when it is strongly activated and sends backwards across its synapses, telling the terminals that feed it to release less; they are the brain's own version of the molecules that cannabis mimics.

The best studied is 2-arachidonoylglycerol (2-AG); anandamide is the other. Neither is stored in vesicles. When the receiving neuron's calcium rises (after strong depolarisation) or certain metabotropic receptors are activated, enzymes in its membrane make 2-AG, which diffuses out to presynaptic terminals and binds CB1 receptors, among the most abundant metabotropic receptors in the brain. CB1 activation inhibits the terminal's calcium channels and so reduces release for seconds, or for much longer when it drives long-term depression. An enzyme in the terminal (monoacylglycerol lipase) then breaks 2-AG down.

It lets a neuron silence its own inputs. In depolarisation-induced suppression of inhibition (DSI), a pyramidal cell that fires hard briefly turns down the GABA release onto itself, and in the opposite case (DSE) the glutamate release.

CB1 receptors are dense on certain interneurons and on many excitatory terminals, in the cortex, hippocampus, basal ganglia and cerebellum, which is why cannabis affects memory, movement and appetite.

THC, the main active compound of cannabis, is a partial agonist at CB1 and acts everywhere at once, without the timing and location of the brain's own on-demand signal.

Endocannabinoids run the synapse in reverse.

The receiving cell, when it is driven hard, reaches back and turns down its own input, a feedback loop that information normally does not travel.

Questions: 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.