Abstract
The adult mammalian brain can produce new neurons in a process called adult neurogenesis, which occurs mainly in the subventricular zone (SVZ) and in the hippocampal dentate gyrus (DG). Brain-derived neurotrophic factor (BDNF) signaling and cannabinoid type 1 and 2 receptors (CB1R and CB2R) have been shown to independently modulate neurogenesis, but how they may interact is unknown. We now used SVZ and DG neurosphere cultures from early (P1-3) postnatal rats to study the CB1R and CB2R crosstalk with BDNF in modulating neurogenesis. BDNF promoted an increase in SVZ and DG stemness and cell proliferation, an effect blocked by a CB2R selective antagonist. CB2R selective activation promoted an increase in DG multipotency, which was inhibited by the presence of a BDNF scavenger. CB1R activation induced an increase in SVZ and DG cell proliferation, being both effects dependent on BDNF. Furthermore, SVZ and DG neuronal differentiation was facilitated by CB1R and/or CB2R activation and this effect was blocked by sequestering endogenous BDNF. Conversely, BDNF promoted neuronal differentiation, an effect abrogated in SVZ cells by CB1R or CB2R blockade while in DG cells was inhibited by CB2R blockade. We conclude that endogenous BDNF is crucial for the cannabinoid-mediated effects on SVZ and DG neurogenesis. On the other hand, cannabinoid receptor signaling is also determinant for BDNF actions upon neurogenesis. These findings provide support for an interaction between BDNF and endocannabinoid signaling to control neurogenesis at distinct levels, further contributing to highlight novel mechanisms in the emerging field of brain repair.
Highlights
Constitutive neurogenesis occurs in the adult mammalian brain where neural stem/progenitor cells (NSPC) are able to differentiate into three neural lineages, neurons, astrocytes and oligodendrocytes (Gage, 2000; Gross, 2000)
They consist of spheroid clones of NSPCs that express both Sox2 and Nestin and that are able to differentiate into neurons, expressing immature neuronal markers, such as doublecortin and βIII tubulin and mature neuronal markers, such as Neuronal Nuclei (NeuN) (Rodrigues et al, 2017)
To investigate the ability of Brain-derived neurotrophic factor (BDNF) and cannabinoid receptor ligands to modulate the cell-fate of subventricular zone (SVZ) cells, a Sox2 cellpair assay was performed in SVZ cells plated for 24 h in medium supplemented or not with receptor ligands (Figure 1A)
Summary
Constitutive neurogenesis occurs in the adult mammalian brain where NSPC are able to differentiate into three neural lineages, neurons, astrocytes and oligodendrocytes (Gage, 2000; Gross, 2000). These multipotent cells exhibit properties of self-renewal and cell proliferation that allow the maintenance of their own pool (Ma et al, 2009). BDNF and CBR Modulation of Neurogenesis the hippocampus These regions are packed with NSPC that originate neuroblasts which migrate toward their final destinations, where they differentiate into mature neurons and are integrated into the neuronal circuitry (Lledo et al, 2006; Zhao et al, 2008; Ming and Song, 2011). There is still a lack of knowledge regarding the key factors that regulate each step of postnatal neurogenesis
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