Endocannabinoids promote neurite outgrowth.

Endocannabinoids have a generally depressive activity at adult synapses, but one of their receptors, CB1, is also expressed in the embryonic nervous system. On page 481, Williams et al. report a possible function for these CB1 receptors—they may respond to signals produced by FGF receptor activation. Several cell adhesion molecules promote axon outgrowth via activation of the FGF receptor, and the new work is the first demonstration of cross-talk between this and the endocannabinoid system.

The FGF receptor signaling cascade stimulates the hydrolysis of diacylglycerol (DAG), which is followed by calcium influx and axonal growth. Williams et al. focus on how DAG hydrolysis leads to calcium influx. As the first step of DAG hydrolysis produces the CB1 receptor agonist 2-arachidonylglycerol, the authors focused on the endocannabinoid system as a possible link. They found that, in rat neurons, CB1 antagonists inhibit the FGF2-stimulated neurite outgrowth response, and CB1 agonists stimulated neurite outgrowth in a manner that required calcium influx, indicating cross-talk between the two systems.

The mediation of tyrosine kinase receptor signals might be a general function of the endocannabinoid system during development. Several CB1 receptor agonists are already being tested as drugs for their neuroprotective activity, and the new results suggest that, in addition to preventing neuronal death, these compounds might also be able to stimualte axonal regeneration following an injury. ▪