Δ9‐Tetrahydrocannabinol promotes oligodendrocyte development and CNS myelination in vivo

• Published in: Glia 2021-03, Vol.69 (3), p.532-545
• Main Authors: Huerga‐Gómez, Alba, Aguado, Tania, Sánchez‐de la Torre, Aníbal, Bernal‐Chico, Ana, Matute, Carlos, Mato, Susana, Guzmán, Manuel, Galve‐Roperh, Ismael, Palazuelos, Javier
• Format: Article
• Language: English
• Subjects: Animal models; Bioactive compounds; Cannabinoid CB1 receptors; Cannabinoid CB2 receptors; cannabinoid receptors; cannabinoids; Cannabis; CB1; CB2; Cell cycle; Cell differentiation; Demyelination; Developmental stages; Differentiation; Embryogenesis; mTORC1; Myelination; oligodendrocyte precursor cells; Pharmacology; Rapamycin; Receptors; Signal transduction; Substantia alba; Tetrahydrocannabinol; THC; TOR protein
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23911

Δ9‐Tetrahydrocannabinol (THC), the main bioactive compound found in the plant Cannabis 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 CB1 and CB2 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 vivo. Main Points The phytocannabinoid THC induces oligodendrocyte precursor cell differentiation during postnatal development. THC promotes CNS myelination through cannabinoid CB1 and CB2 receptor activation.