Perinatal LC-ω-3-PUFA supplementation offsets prenatal THC-induced cognitive deficit via sex-specific modulation of hippocampal neuroplasticity

Long-chain polyunsaturated fatty acids (LC-PUFAs) are crucial for brain development, with omega-3 species supporting neuronal membrane architecture, synaptogenesis and cognitive maturation, and omega-6 species linking lipid metabolism to neuronal signalling via the endocannabinoid system (ECS), the network of receptors, lipid mediators, and enzymatic pathways that orchestrate neurodevelopmental processes. Prenatal exposure to Delta(9)-tetrahydrocannabinol (THC), the psychoactive component of cannabis, impairs memory and disrupts hippocampal plasticity markers affecting the excitatory/inhibitory (E/I) balance, in a sex-dependent manner. This dysregulation is closely associated with a lipid shift favouring omega-6-derived mediators, leading to ECS imbalance. We investigated whether perinatal LC-w-3-PUFA supplementation could prevent prenatal THC-induced neurodevelopmental deficits. Pregnant rats received THC (2 mg/kg, gestational days 5-20) and either a standard or LC omega-3-PUFA-enriched diet (omega-3/omega-6 ratio = 1.4) from gestation through lactation. Adolescent offspring were evaluated for hippocampus-dependent memory (Novel object recognition) and gene expression of hippocampal plasticity markers (NR1, mGluR5, CB1R, Nlgn-1/2/3) and endocannabinoid metabolising enzymes (DAGLa, NAPE-PLD, MAGL, FAAH). LC-omega-3-PUFAs prevented prenatal THC-induced memory impairment in both sexes. Molecular analyses revealed sex-specific recovery mechanisms. In males, LC-omega-3-PUFAs counteracted prenatal THC-induced synaptic hyperexcitability by restoring NR1, mGluR5, and CB1R expression, reducing Nlgn-1 and enhancing the Nlgn-3 levels, together with increased NAPE-PLD expression. In females, LC-omega-3-PUFAs rebalanced the prenatal THC-induced predominant inhibitory shift by reducing Nlgn-2/-3- and NAPE-PLD expression levels. These findings identify perinatal LC-omega-3-PUFA supplementation as a safe, effective nutritional strategy to counteract THC-induced neurodevelopmental vulnerability by restoring ECS balance and supporting sex-specific neuronal plasticity and cognitive integrity.