Abstract
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 CB(1) 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 CB(1)-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(1) 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.
Highlights
During the last decade the endocannabinoid system has been characterized by identification of its endogenous ligands anandamide (AEA)1 and 2-arachidonoylglycerol (2AG) [1, 2], cloning of their specific seven transmembrane receptors CB1 and CB2
Anandamide Inhibits Neuronal Differentiation via CB1 —We monitored the differentiation of cortical neuron progenitors from 17-day-old rat embryos into mature neurons
Endocannabinoids and the Regulation of Neurogenesis— Here we show that endocannabinoids are able to inhibit neuronal differentiation in different cellular models in vitro, and this correlates with their ability to inhibit adult hippocampal neurogenesis in vivo
Summary
Materials—The following materials were kindly donated: plasmids encoding Rap1V12, RasV12, and B-Raf Vollum Institute, Portland, OR), GST-RalGDS fusion protein I. Bonner at the National Institute of Health, Bethesda, MD, and Dr Z. Vogel at The Weizmann Institute, Rehovot, Israel), SR141716 (Sanofi Synthelabo, Montpellier, France), anti-human CB1 polyclonal antibody University of Washington, Seattle, WA) and HU-210 AEA and 2AG were from Cayman Chemicals (Ann Arbor, MI); rabbit polyclonal
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