RT Journal Article
T1 Cannabinoid CB1 receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice
A1 Sánchez De La Torre, Aníbal
A1 Aguado Sánchez, Tania
A1 Huerga-Gómez, Alba
A1 Santamaría, Silvia
A1 Gentile, Antonietta
A1 Chara, Juan Carlos
A1 Matute, Carlos
A1 Monory, Krisztina
A1 Mato, Susana
A1 Guzmán Pastor, Manuel
A1 Lutz, Beat
A1 Galve Roperh, Ismael
A1 Palazuelos Diego, Javier
AB Cannabinoids are known to modulate oligodendrogenesis and developmental CNS myelination. However, the cell-autonomous action of these compounds on oligodendroglial cells in vivo, and the molecular mechanisms underlying these effects have not yet been studied. Here, by using oligodendroglial precursor cell (OPC)-targeted genetic mouse models, we show that cannabinoid CB1 receptors exert an essential role in modulating OPC differentiation at the critical periods of postnatal myelination. We found that selective genetic inactivation of CB1 receptors in OPCs in vivo perturbs oligodendrogenesis and postnatal myelination by altering the RhoA/ROCK signaling pathway, leading to hypomyelination, and motor and cognitive alterations in young adult mice. Conversely, pharmacological CB1 receptor activation, by inducing E3 ubiquitin ligase-dependent RhoA proteasomal degradation, promotes oligodendrocyte development and CNS myelination in OPCs, an effect that was not evident in OPC-specific CB1 receptordeficient mice. Moreover, pharmacological inactivation of ROCK in vivo overcomes the defects in oligodendrogenesis and CNS myelination, and behavioral alterations found in OPC-specific CB1 receptor-deficient mice. Overall, this study supports a cellautonomous role for CB1 receptors in modulating oligodendrogenesis in vivo, which may have a profound impact on the scientific knowledge and therapeutic manipulation of CNS myelination by cannabinoids.
PB Springer Nature
SN 2041-4889
YR 2022
FD 2022
LK https://hdl.handle.net/20.500.14352/88941
UL https://hdl.handle.net/20.500.14352/88941
LA eng
NO Sánchez-de la Torre, A., Aguado, T., Huerga-Gómez, A. et al. Cannabinoid CB1 receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice. Cell Death Dis 13, 585 (2022). https://doi.org/10.1038/s41419-022-05032-z
NO Ministerio Economía y Transformación Digital (España)
NO Comunidad de Madrid
NO Institituto de Salud Carlos III 
NO Eusko Jaurlaritza
NO European Commission
NO Multiple Sclerosis Research Foundation (France)
DS Docta Complutense
RD 1 sept 2024