Delta(9)-Tetrahydrocannabinol Promotes Oligodendrocyte Development and CNS Myelination in Vivo

Delta(9)-Tetrahydrocannabinol (THC), the main bioactive compound found in the plantCannabis sativa, exerts its effects by activating cannabinoid receptors present in many neural cells. Cannabinoid receptors are also physiologically engaged by endogenous cannabinoid compounds, the so-called endocannabinoids. Specifically, the endocannabinoid 2-arachidonoylglycerol has been highlighted as an important modulator of oligodendrocyte (OL) development at embryonic stages and in animal models of demyelination. However, the potential impact of THC exposure on OL lineage progression during the critical periods of postnatal myelination has never been explored. Here, we show that acute THC administration at early postnatal ages in mice enhanced OL development and CNS myelination in the subcortical white matter by promoting oligodendrocyte precursor cell cycle exit and differentiation. Mechanistically, THC-induced-myelination was mediated by CB(1)and CB(2)cannabinoid receptors, as demonstrated by the blockade of THC actions by selective receptor antagonists. Moreover, the THC-mediated modulation of oligodendroglial differentiation relied on the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, as mTORC1 pharmacological inhibition prevented the THC effects. Our study identifies THC as an effective pharmacological strategy to enhance oligodendrogenesis and CNS myelination in vivoCentro de Investigacion Biomedica en Red Enfermedades Neurodegenerativas, Grant/Award Numbers: CB06/0005/0076, CB06/05/0005; Comunidad de Madrid, Grant/Award Numbers: 2016-T1/BMD-1060, PEJD2017-PRE/BMD-3703; Eusko Jaurlaritza, Grant/Award Numbers: IT1203-19, PIBA19-0059; Fundacion Tatiana Perez de Guzman el Bueno; FEDER and Instituto de Salud Carlos III, Grant/Award Numbers: PI18-00941, PI18/00513; Ministerio de Economia y Competitividad, Grant/Award Numbers: RTI2018-095311-B-I00, SAF2016-75292-R, SAF2017-83516-