ENDOCANNABINOID DYSREGULATION CONTRIBUTES TO COGNITIVE IMPAIRMENT AND MYELINATION DEFICITS IN AN EXPERIMENTAL MODEL OF FASD

Fetal Alcohol Spectrum Disorders (FASD) are associated with persistent cognitive deficits and abnormal brain myelination. Evidence suggests that the endocannabinoid (eCB) system contributes to myelination and is dysregulated in FASD. This study examined whether eCB modulation by JZL-184 (a monoacylglycerol lipase (MAGL) inhibitor that elevates 2-arachidonoylglycerol; 2-AG) or cannabidiol (CBD; an indirect modulator of eCB signaling) improves recognition memory and reduces hippocampal myelination deficits in male and female rats with an established FASD model. Wistar rats received ethanol (5 g/kg/day, intragastric) on postnatal days (PND) 4–9 (human third-trimester equivalent). From PND25–32, animals were treated with JZL-184 (4 or 8 mg/kg, intraperitoneal) or CBD (10 mg/kg, intraperitoneal). Recognition memory was assessed in the novel object recognition (NOR) test. Hippocampal eCB levels were measured by liquid chromatography–mass spectrometry (LC-MS) on PND22, and myelin-related proteins were quantified by enzyme-linked immunosorbent assay (ELISA) on PND22 and PND50. Ethanol exposure reduced myelin markers (myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), myelin and lymphocyte protein (MAL), and 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase)), mainly in males, increased anandamide (AEA) in females, and decreased 2-AG and 1-arachidonoylglycerol (1-AG) in both sexes at PND22. FASD rats showed impaired object recognition, with persistently reduced MBP, MAL and CNPase in males. JZL-184 (8 mg/kg) improved recognition memory and tended to increase MAL, whereas CBD had no significant effects. These findings indicate sex-dependent hippocampal myelination deficits after early ethanol exposure and suggest that enhancing MAGL/2-AG signaling may partially restore cognitive function and myelin-related alterations in FASD.