Sarikahya Mohammed H, Cousineau Samantha L, De Felice Marta, Szkudlarek Hanna J, Lee Kendrick, Doktor Aleksandra, Alcaide Amanda, DeVuono Marieka V, Dembla Anubha, Wong Karen, Balarajah Mathanke, Vanin Sebastian, Youssef Miray, Zhaksylyk Kuralay, Machado Madeline, Mahmood Haseeb, Schmid Susanne, Yeung Ken K-C, Hardy Daniel B, Rushlow Walter, Laviolette Steven R
Addiction Research Group, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada.
Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada.
Mol Psychiatry. 2025 Jul 28. doi: 10.1038/s41380-025-03113-x.
Prenatal Δ9-tetrahydrocannabinol exposure (PTE) poses long-lasting neuropsychiatric risks, as evidenced by clinical and preclinical studies, yet the neurobiological mechanisms remain poorly defined. Emerging evidence implicates the neurolipidome, a critical mediator of neurodevelopment and endocannabinoid signaling, as a potential contributor. Here, we demonstrate that dietary omega-3 fatty acid supplementation sex-selectively ameliorates neurodevelopmental deficits induced by PTE in a Wistar rat model. Omega-3 supplementation reduced cognitive and emotional disturbances in male offspring and normalized many neuronal and neurochemical abnormalities in the prefrontal cortex, nucleus accumbens, and ventral hippocampus. However, lipidomic analyses, regardless of omega-3 supplementation, uncovered pronounced, sex-specific PTE-induced disruptions in pathways critical for synaptic integrity and neurodevelopment, including those related to the endocannabinoid system. These findings provide new insights into the interplay between lipid metabolism and the endocannabinoid system in the context of PTE.
产前Δ9-四氢大麻酚暴露（PTE）会带来长期的神经精神风险，临床和临床前研究已证明了这一点，但神经生物学机制仍不清楚。新出现的证据表明，神经脂质组作为神经发育和内源性大麻素信号传导的关键介质，可能是一个促成因素。在此，我们证明，在Wistar大鼠模型中，饮食补充ω-3脂肪酸可按性别选择性地改善PTE诱导的神经发育缺陷。补充ω-3可减少雄性后代的认知和情绪障碍，并使前额叶皮质、伏隔核和腹侧海马中的许多神经元和神经化学异常恢复正常。然而，脂质组学分析发现，无论是否补充ω-3，PTE都会在对突触完整性和神经发育至关重要的途径中引起明显的、性别特异性的破坏，包括与内源性大麻素系统相关的途径。这些发现为PTE背景下脂质代谢与内源性大麻素系统之间的相互作用提供了新的见解。
