Serrano Maitane, Saumell-Esnaola Miquel, Ocerin Garazi, García Del Caño Gontzal, Soria-Gómez Edgar, Mimenza Amaia, Puente Nagore, Bonilla-Del Río Itziar, Ramos-Uriarte Almudena, Reguero Leire, Christie Brian R, Rodríguez de Fonseca Fernando, Rodríguez-Arias Marta, Gerrikagoitia Inmaculada, Grandes Pedro
Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, 48940 Leioa, Spain.
Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, 48940 Leioa, Spain.
Int J Mol Sci. 2025 Jun 9;26(12):5507. doi: 10.3390/ijms26125507.
Adolescent binge drinking has lasting behavioral consequences by disrupting the endocannabinoid system (ECS) and depleting brain omega-3. The natural accumulation of omega-3 fatty acids in cell membranes is crucial for maintaining the membrane structure, supporting interactions with the ECS, and restoring synaptic plasticity and cognition impaired by prenatal ethanol (EtOH) exposure. However, it remains unclear whether omega-3 supplementation can mitigate the long-term effects on the ECS, endocannabinoid-dependent synaptic plasticity, and cognition following adolescent binge drinking. Here, we demonstrated that omega-3 supplementation during EtOH withdrawal increases CB1 receptors in hippocampal presynaptic terminals of male mice, along with the recovery of receptor-stimulated [S]GTPγS binding to Gαi/o proteins. These changes are associated with long-term potentiation (LTP) at excitatory medial perforant path (MPP) synapses in the dentate gyrus (DG), which depends on anandamide (AEA), transient receptor potential vanilloid 1 (TRPV1), and N-methyl-D-aspartate (NMDA) receptors. Finally, omega-3 intake following binge drinking reduced the time and number of errors required to locate the escape box in the Barnes maze test. Collectively, these findings suggest that omega-3 supplementation restores Barnes maze performance to levels comparable to those of control mice after adolescent binge drinking. This recovery is likely mediated by modulation of the hippocampal ECS, enhancing endocannabinoid-dependent excitatory synaptic plasticity.
青少年暴饮会破坏内源性大麻素系统（ECS）并消耗大脑中的omega-3，从而产生持久的行为后果。细胞膜中omega-3脂肪酸的自然积累对于维持膜结构、支持与ECS的相互作用以及恢复因产前乙醇（EtOH）暴露而受损的突触可塑性和认知至关重要。然而，omega-3补充剂是否能减轻青少年暴饮对ECS、内源性大麻素依赖性突触可塑性和认知的长期影响仍不清楚。在此，我们证明在EtOH戒断期间补充omega-3可增加雄性小鼠海马突触前终末中的CB1受体，同时使受体刺激的[S]GTPγS与Gαi/o蛋白的结合恢复。这些变化与齿状回（DG）中兴奋性内侧穿通通路（MPP）突触处的长时程增强（LTP）有关，LTP依赖于花生四烯乙醇胺（AEA）、瞬时受体电位香草酸亚型1（TRPV1）和N-甲基-D-天冬氨酸（NMDA）受体。最后，暴饮后摄入omega-3减少了在Barnes迷宫测试中找到逃生箱所需的时间和错误次数。总体而言，这些发现表明，补充omega-3可使青少年暴饮后Barnes迷宫测试的表现恢复到与对照小鼠相当的水平。这种恢复可能是通过调节海马ECS介导的，增强了内源性大麻素依赖性兴奋性突触可塑性。
