2-ARACHIDONOYLGLYCEROL-MEDIATED CROSSTALK BETWEEN ASTROCYTES AND OLIGODENDROCYTES ORCHESTRATES OLIGODENDROCYTE LINEAGE CELLS FATE DURING MYELIN DEVELOPMENT AND REGENERATION

Cannabinoids have consistently demonstrated to be key modulators of oligodendrocyte (OL) cell fate and myelin homeostasis, both during development and in neuropathological conditions. One of the main strategies employed to date involves elevating the endocannabinoid tone of 2-arachidonoylglycerol (2-AG) through the pharmacological inhibition of monoacylglycerol lipase (MGL), the main enzyme responsible for its degradation. Converging evidence highlights that the interaction between astroglial cells and OL modulates OL cell fate and maintains myelin homeostasis under physiological and pathological contexts. In particular, astroglial MGL emerges as a metabolic hub integrating endocannabinoid and eicosanoid signaling pathways.
Here, we investigated how selective inactivation of astroglial MGL influences OL lineage dynamics and myelin stability during postnatal development and during remyelination following cuprizone-induced demyelination. Using a genetic mouse model, we found that selective astroglial MGL inactivation promotes OL differentiation and enhances postnatal myelination through 2-AG-dependent activation of CB₁ receptors on NG2 cells. To explore the role of astroglial MGL in a pathological context, we employed the cuprizone demyelination model and observed that astroglial MGL deficiency enhances OL differentiation and myelin regeneration and alleviates gliosis and axonal damage.
By tuning 2-AG availability, astrocytes coordinate intercellular signaling that enhances oligodendrogenesis and myelin homeostasis; collectively, this positions astrocytic 2-AG metabolism as a critical regulatory node, and targeting this glial metabolic axis opens promising avenues for therapeutic modulation of demyelinating diseases.