Activation of Type 1 Cannabinoid Receptor CB1R Promotes Neurogenesis in Murine Subventricular Zone Cell CulturesReportar como inadecuado




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The endocannabinoid system has been implicated in the modulation of adult neurogenesis. Here, we describe the effect of type 1 cannabinoid receptor CB1R activation on self-renewal, proliferation and neuronal differentiation in mouse neonatal subventricular zone SVZ stem-progenitor cell cultures. Expression of CB1R was detected in SVZ-derived immature cells Nestin-positive, neurons and astrocytes. Stimulation of the CB1R by R-+-Methanandamide R-m-AEA increased self-renewal of SVZ cells, as assessed by counting the number of secondary neurospheres and the number of Sox2+-+ cell pairs, an effect blocked by Notch pathway inhibition. Moreover, R-m-AEA treatment for 48 h, increased proliferation as assessed by BrdU incorporation assay, an effect mediated by activation of MAPK-ERK and AKT pathways. Surprisingly, stimulation of CB1R by R-m-AEA also promoted neuronal differentiation without affecting glial differentiation, at 7 days, as shown by counting the number of NeuN-positive neurons in the cultures. Moreover, by monitoring intracellular calcium concentrations Ca2+i in single cells following KCl and histamine stimuli, a method that allows the functional evaluation of neuronal differentiation, we observed an increase in neuronal-like cells. This proneurogenic effect was blocked when SVZ cells were co-incubated with R-m-AEA and the CB1R antagonist AM 251, for 7 days, thus indicating that this effect involves CB1R activation. In accordance with an effect on neuronal differentiation and maturation, R-m-AEA also increased neurite growth, as evaluated by quantifying and measuring the number of MAP2-positive processes. Taken together, these results demonstrate that CB1R activation induces proliferation, self-renewal and neuronal differentiation from mouse neonatal SVZ cell cultures.



Autor: Sara Xapelli, Fabienne Agasse , Laura Sardà-Arroyo, Liliana Bernardino, Tiago Santos, Filipa F. Ribeiro, Jorge Valero, José Bra

Fuente: http://plos.srce.hr/



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