The endocannabinoid anandamide inhibits neuronal progenitor cell differentiation through attenuation of the Rap1/B-Raf/ERK pathway

Endocannabinoids are neuromodulators that act as retrograde synaptic messengers inhibiting the release of different neurotransmitters in cerebral areas such as hippocampus, cortex, and striatum. However, little is known about other roles of the endocannabinoid system in brain. In the present work we provide substantial evidence that the endocannabinoid anandamide (AEA) regulates neuronal differentiation both in culture and in vivo. Thus AEA, through the CB1 receptor, inhibited cortical neuron progenitor differentiation to mature neuronal phenotype. In addition, human neural stem cell differentiation and nerve growth factor-induced PC12 cell differentiation were also inhibited by cannabinoid challenge. AEA decreased PC12 neuronal-like generation via CB1-mediated inhibition of sustained extracellular signal-regulated kinase (ERK) activation, which is responsible for nerve growth factor action. AEA thus inhibited TrkA-induced Rap1/B-Raf/ERK activation. Finally, immunohistochemical analyses by confocal microscopy revealed that adult neurogenesis in dentate gyrus was significantly decreased by the AEA analogue methanandamide and increased by the CB, antagonist SR141716. These data indicate that endocannabinoids inhibit neuronal progenitor cell differentiation through attenuation of the ERK pathway and suggest that they constitute a new physiological system involved in the regulation of neurogenesis.