LINOLEIC ACID–INDUCED ASTROCYTIC ENDOCANNABINOID RELEASE: EXPLORING MOLECULAR MECHANISMS AND POTENTIAL SUBTYPE SPECIFICITY

The lipid signaling molecules endocannabinoids (eCBs), together with cannabinoid receptors, form a widely distributed signaling system that regulates most brain functions: the endocannabinoid system. Although eCB synthesis has classically been attributed to neurons, astrocytes express the enzymatic machinery required for eCB production, yet their contribution to eCB signaling remains poorly understood. Our recent work demonstrates that astrocytes synthesize and release the eCB 2-arachidonoylglycerol (2-AG) in a calcium-dependent manner requiring diacylglycerol lipase-α (DAGLA). Notably, transcriptomic analysis of publicly available astrocyte single-cell RNA-seq datasets revealed that Dagla-expressing astrocytes are enriched for genes involved in lipid metabolic pathways, particularly linoleic acid (LA) metabolism.
Based on these observations, we hypothesized that LA-metabolizing enzymes constitute a substrate-sensitive machinery enabling astrocytes to detect LA and respond with eCB production. Consistent with this hypothesis, acute LA exposure robustly increases astrocytic 2-AG synthesis and release in vitro, as measured by mass spectrometry and the GRABeCB2.0 sensor. LA similarly enhances eCB production in ex vivo astrocytes, leading to increased eCB signaling onto neighbouring neurons.
Ongoing work aims to (i) define the molecular identity of the LA-responsive astrocytic eCB synthesis pathway and determine whether it is metabolically or signaling driven, (ii) assess whether this machinery is restricted to a specialized astrocyte subtype or broadly conserved, and (iii) evaluate the functional relevance of LA-induced astrocytic eCB release on neuronal activity.
Identifying a specialized cannabinergic astrocyte population could reveal a novel mechanism by which astrocytic endocannabinoid integrate lipid-derived environmental inputs to modulate neuronal activity with potential therapeutic relevance for different diseases.