Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies

Key Points Cannabinoid receptor diversity and signalling in the immature brain are vastly different from those in the adult nervous system. These include the differential localization of, and signal transduction by, cannabinoid receptors and the enzymes that limit endocannabinoid bioavailability. CB1 and CB2 cannabinoid receptors signal neural progenitor proliferation in the developing brain, including gliogenesis, by coupling to mitogenic pathways such as PI3K and ERK. Endocannabinoid hot spots can facilitate the directional migration of postmitotic neurons in the foetal nervous system, as well as of neuroblasts in neurogenic areas of the adult mammalian brain. CB1 cannabinoid receptors, and probably CB2 and TRPV1 receptors, in growth cones signal to modulate steering decisions during directional axonal growth. In part, autocrine signalling by endocannabinoids mediates neurite elongation. Diacylgycerol lipase-dependent endocannabainoid signalling regulates neurogenesis in the adult hippocampus and subventricular zone. Δ 9 -THC affects neuronal development via CB1 cannabinoid receptor-mediated mechanisms, disrupting cytoskeletal integrity, axonal growth and synaptogenesis. Therefore, THC exposure is adverse in developmental contexts. Preclinical evidence suggests that pharmacological activation of cannabinoid receptors might be exploited therapeutically to inhibit tumor growth in glioma patients. Endocannabinoids are involved in regulating neural progenitor cell proliferation, as well as neuronal and glial differentiation. In this Review, Maccarrone, Harkany and colleagues discuss mechanisms of endocannabinoid signalling, the action of plant cannabinoids in the foetal brain, and their exploitation to modulate diseases associated with defective cell cycle control, particularly cancer. Among the many signalling lipids, endocannabinoids are increasingly recognized for their important roles in neuronal and glial development. Recent experimental evidence suggests that, during neuronal differentiation, endocannabinoid signalling undergoes a fundamental switch from the prenatal determination of cell fate to the homeostatic regulation of synaptic neurotransmission and bioenergetics in the mature nervous system. These studies also offer novel insights into neuropsychiatric disease mechanisms and contribute to the public debate about the benefits and the risks of cannabis use during pregnancy and in adolescence.