Brain-Derived Neurotrophic Factor (BDNF) Role in Cannabinoid-Mediated Neurogenesis

Filipa Fiel Ferreira, Filipa F. Ribeiro, Rui S. Rodrigues, Ana Maria Sebastião, Sara Xapelli
Frontiers in Cellular Neuroscience. 2018-11-28; 12:
DOI: 10.3389/fncel.2018.00441

1. Front Cell Neurosci. 2018 Nov 28;12:441. doi: 10.3389/fncel.2018.00441.
eCollection 2018.

Brain-Derived Neurotrophic Factor (BDNF) Role in Cannabinoid-Mediated
Neurogenesis.

Ferreira FF(1)(2), Ribeiro FF(1)(2), Rodrigues RS(1)(2), Sebastião AM(1)(2),
Xapelli S(1)(2).

Author information:
(1)Instituto de Farmacologia e Neurociências, Faculdade de Medicina,
Universidade de Lisboa, Lisbon, Portugal.
(2)Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina,
Universidade de Lisboa, Lisbon, Portugal.

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.