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Cannabinoids and BDNF: modulators of Postnatal Neurogenesis

Rui S. Rodrigues1, 2, Filipa F. Ribeiro1, 2, Filipa F. Ferreira1, 2, Sandra H. Vaz1, 2, Ana M. Sebastião1, 2 and Sara Xapelli1, 2*
  • 1 Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Portugal
  • 2 Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Portugal

Postnatal neurogenesis occurs in restricted areas of the adult mammalian brain and is a process regulated by several neuromodulators like neurotrophins and cannabinoids. Herein, we aimed at unravelling the role of cannabinoid type 1 and 2 receptors (CB1R and CB2R) and brain-derived neurotrophic factor (BDNF) on subventricular zone (SVZ) and dentate gyrus (DG) postnatal neurogenesis. Using neurospheres from early postnatal Sprague-Dawley rats (P1-3) we found that BDNF treatment promoted self-renewing divisions of SVZ and DG cells, an effect abolished in the presence of a CB2R selective antagonist. CB2R activation increased DG self-renewal capacity, an effect abrogated by endogenous BDNF removal. DG cell proliferation was found to be significantly increased after CB1R+CB2R co-activation or BDNF treatment, effects abolished by scavenging endogenous BDNF or by CB2R antagonism, respectively. SVZ cell proliferation was enhanced by BDNF treatment or CB1R activation. This increase in cell proliferation was blocked in the presence of CB1R or CB2R antagonists or a BDNF scavenger. BDNF promoted neuronal differentiation, which was blocked in SVZ by CB1R or CB2R antagonists, and only by CB2R antagonism in DG. Concomitantly, CB1R and/or CB2R activation promoted SVZ and DG neuronal differentiation, an effect dependent on endogenous BDNF. Modulation of CB1R and/or CB2R was also found to shape SVZ and DG neuronal maturation processes, namely neurite outgrowth and branching. Overall, the actions of cannabinoids on proliferation and differentiation of SVZ and DG-derived cells were shown to involve a close interaction between CB1R and CB2R, suggesting a fundamental role of this crosstalk in modulating postnatal neurogenesis. Moreover, these cannabinoid-mediated effects were shown to be highly dependent on the presence of endogenous BDNF whereas CB2R played a preponderant role in regulating some of the BDNF actions on neurogenesis. Taken together, we demonstrated that BDNF, CB1R and CB2R are important regulators of neural stem/progenitor cell dynamics by revealing new layers of interaction between cannabinoid receptors and BDNF responsible to fine-tune early SVZ and DG postnatal neurogenesis, cross-antagonism phenomena being evident.

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Acknowledgements

This work was supported by LISBOA-01-0145-FEDER-007391, project co-funded by FEDER, through Programa Operacional Regional de Lisboa, PORTUGAL 2020 and Fundação para a Ciência e a Tecnologia (FCT) Portugal (PTDC/DTP-FTO/3346/2014). RR (SFRH/BD/129710/2017), FR (SFRH/BD/74662/2010), SV (SFRH/BPD/81627/2011), and SX (SFRH/BPD/76642/2011 and IF/01227/2015) were in receipt of a fellowship from FCT. AS thanks the H2020 Twinning Action from EU (SynaNet 692340). BDNF was kindly given by Regeneron.

Keywords: postnatal neurogenesis, Subventricular zone, Dentate Gyrus, cannabinoid receptors, Brain-derived growth factor

Conference: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019), Lisboa, Portugal, 30 May - 1 Jun, 2019.

Presentation Type: Poster presentation

Topic: Neurodevelopment / Regeneration

Citation: Rodrigues RS, Ribeiro FF, Ferreira FF, Vaz SH, Sebastião AM and Xapelli S (2019). Cannabinoids and BDNF: modulators of Postnatal Neurogenesis. Front. Cell. Neurosci. Conference Abstract: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019). doi: 10.3389/conf.fncel.2019.01.00035

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Received: 16 Apr 2019; Published Online: 27 Sep 2019.

* Correspondence: Dr. Sara Xapelli, Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Lisbon, 1649-028, Portugal, sxapelli@medicina.ulisboa.pt