The brake
Game · the synapse
▶ Play this chapter The script
Every line as it is spoken in the film, in order.
This is a synapse. You have about a hundred trillion of them. Messages cross the gap one way, from the top cell to the bottom one.
Right now the top cell is shouting. If the bottom cell gets too excited, it gets hurt. Keep it out of the red. Press and hold to brake.
Press and hold anywhere to make the brake.
See that? The bottom cell carves 2-AG out of its own membrane and sends it backward. Against the traffic.
Too hot. Brake sooner.
You kept it safe. That's the backward signal. Your cells do it on their own, on demand, the moment they need it.
Now the same cell, in a mouse born without CB1 on these cells. Same brake. Try it.
The brake has nowhere to land. In mice like this, a seizure-causing toxin hit much harder. Your keys are a built-in defense.
Now it's yours. Add THC. Block the enzyme. Turn the shouting up. Switch on automatic. See what happens.
THC holds the locks part of the way open, whether the cell asked or not. And your own brake has a harder time getting through. Now picture that everywhere at once. That's the high.
Block MAGL, and the brake lingers. Your own key lasts longer.
Rimonabant. The brake can't land, even with CB1 there.
On automatic, the cell brakes itself, only when it needs to. That's what your cells are doing right now.
That's the secret, up close: a message that runs backward, made when it's needed and gone in moments. Next: what happens when the plant's key shows up.
Sources
Every claim in this chapter with its grade: E established · M emerging (one or two studies, or animals only) · F framework.
- EDinh TP et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. PNAS 2002;99:10819–24. (MAGL) link
- EGulyas AI et al. Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci 2004;20:441–58. (MAGL sits in the sending terminal) link
- EKreitzer AC, Regehr WG. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 2001;29:717–27. link
- MLaaris N, Good CH, Lupica CR. Δ9-THC is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus. Neuropharmacology 2010;59:121–7. (mice) link
- EMarsicano G et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 2003;302:84–8. (mice lacking CB1 in forebrain principal neurons; kainic acid seizures) link
- EMonory K et al. The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 2006;51:455–66. (CB1 on glutamatergic neurons is necessary and sufficient for protection; mice) link
- EOhno-Shosaku T, Maejima T, Kano M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 2001;29:729–38. link
- EPakkenberg B et al. Aging and the human neocortex. Exp Gerontol 2003;38:95–9. (about 0.15 × 10¹⁵ synapses in the neocortex) link
- EPertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-THC, cannabidiol and Δ9-THCV. Br J Pharmacol 2008;153:199–215. (THC is a CB1 partial agonist) link
- ERinaldi-Carmona M et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 1994;350:240–4. (rimonabant) link
- MStraiker A, Mackie K. Depolarization-induced suppression of excitation in murine autaptic hippocampal neurones. J Physiol 2005;569:501–17. (THC fails to inhibit, yet occludes 2-AG-mediated DSE; mouse neurons) link
- ETanimura A et al. The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase α mediates retrograde suppression of synaptic transmission. Neuron 2010;65:320–7. (mice) link
- EWilson RI, Nicoll RA. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 2001;410:588–92. link
- ESchikorski T, Stevens CF. Quantitative ultrastructural analysis of hippocampal excitatory synapses. J Neurosci 1997;17:5858–67. (Mouse CA1: about 200 vesicles per bouton, about 10 docked per active zone, active zones about 0.04 µm².) link
- ESavtchenko LP, Rusakov DA. The optimal height of the synaptic cleft. PNAS 2007;104:1823–8. (An optimum of about 12–20 nm, consistent with electron microscopy of central synapses.) link
- ESpacek J, Harris KM. Three-dimensional organization of smooth endoplasmic reticulum in hippocampal CA1 dendrites and dendritic spines of the immature and mature rat. J Neurosci 1997;17:190–203. (Over 80% of large mushroom spines had a spine apparatus.) link
- ESteward O, Levy WB. Preferential localization of polyribosomes under the base of dendritic spines in granule cells of the dentate gyrus. J Neurosci 1982;2:284–91. link