TY - JOUR
T1 - Type-1 (CB1) Cannabinoid Receptor Promotes Neuronal Differentiation and Maturation of Neural Stem Cells
AU - Compagnucci, Claudia
AU - Di Siena, Sara
AU - Bustamante, Maria Blaire
AU - Di Giacomo, Daniele
AU - Di Tommaso, Monia
AU - Maccarrone, Mauro
AU - Grimaldi, Paola
AU - Sette, Claudio
PY - 2013/1/29
Y1 - 2013/1/29
N2 - Neural stem cells (NSCs) are self-renewing cells that can differentiate into multiple neural lineages and repopulate regions of the brain after injury. We have investigated the role of endocannabinoids (eCBs), endogenous cues that modulate neuronal functions including neurogenesis, and their receptors CB1 and CB2 in mouse NSCs. Real-time PCR and Western blot analyses indicated that CB1 is present at higher levels than CB2 in NSCs. The eCB anandamide (AEA) or the CB1-specific agonist ACEA enhanced NSC differentiation into neurons, but not astrocytes and oligodendrocytes, whereas the CB2-specific agonist JWH133 was ineffective. Conversely, the effect of AEA was inhibited by CB1, but not CB2, antagonist, corroborating the specificity of the response. CB1 activation also enhanced maturation of neurons, as indicated by morphometric analysis of neurites. CB1 stimulation caused long-term inhibition of the ERK1/2 pathway. Consistently, pharmacological inhibition of the ERK1/2 pathway recapitulated the effects exerted by CB1 activation on neuronal differentiation and maturation. Lastly, gene array profiling showed that CB1 activation augmented the expression of genes involved in neuronal differentiation while decreasing that of stemness genes. These results highlight the role of CB1 in the regulation of NSC fate and suggest that its activation may represent a pro-neuronal differentiation signal.
AB - Neural stem cells (NSCs) are self-renewing cells that can differentiate into multiple neural lineages and repopulate regions of the brain after injury. We have investigated the role of endocannabinoids (eCBs), endogenous cues that modulate neuronal functions including neurogenesis, and their receptors CB1 and CB2 in mouse NSCs. Real-time PCR and Western blot analyses indicated that CB1 is present at higher levels than CB2 in NSCs. The eCB anandamide (AEA) or the CB1-specific agonist ACEA enhanced NSC differentiation into neurons, but not astrocytes and oligodendrocytes, whereas the CB2-specific agonist JWH133 was ineffective. Conversely, the effect of AEA was inhibited by CB1, but not CB2, antagonist, corroborating the specificity of the response. CB1 activation also enhanced maturation of neurons, as indicated by morphometric analysis of neurites. CB1 stimulation caused long-term inhibition of the ERK1/2 pathway. Consistently, pharmacological inhibition of the ERK1/2 pathway recapitulated the effects exerted by CB1 activation on neuronal differentiation and maturation. Lastly, gene array profiling showed that CB1 activation augmented the expression of genes involved in neuronal differentiation while decreasing that of stemness genes. These results highlight the role of CB1 in the regulation of NSC fate and suggest that its activation may represent a pro-neuronal differentiation signal.
UR - http://www.scopus.com/inward/record.url?scp=84872800314&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872800314&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0054271
DO - 10.1371/journal.pone.0054271
M3 - Article
C2 - 23372698
AN - SCOPUS:84872800314
VL - 8
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 1
M1 - e54271
ER -