Omega-3 fatty acids potentiate the endocannabinoid-dependent synaptic plasticity lost after adolescent binge drinking in male mouse dentate gyrus

Adolescence binge drinking impacts on cognition and behavior through the brain endocannabinoid system (ECS). Dietary long-chain polyunsaturated omega-3 (n-3) fatty acids increase hippocampal synaptic transmission and improve memory functions. Strikingly, alcohol (EtOH) decreases n-3 in the brain, having a negative effect on synaptic plasticity. Because adolescent binge drinking causes long-term impairment of the cannabinoid-dependent synaptic plasticity at the excitatory medial perforant path (MPP) synapses of the hippocampal dentate gyrus (Peñasco et al., 2020), we hypothesize that n-3 could recover this functional deficit of the adult brain. To investigate it, we used 4-week-old male mice (C57BL/6J) and exposed them to drinking-in-the-dark from PND 32 to 59 (H2O and OH mice groups). During abstinence (PND 60-73), half of them were fed a n-3 supplemented diet (EPA 2.7% + DHA 2%) (n-3-H2O, n-3-OH).Light microscopic immunohistochemistry showed that optical density of CB1 receptor staining in the hippocampus was similar among mice conditions. However, CB1 receptor expression increased in hippocampal synaptosomes of OH, n-3-OH and n-3-H2O. This effect was associated with a CB1 immunogold particle density rise detected in inhibitory synaptic terminals by electron microscopy. CB1 receptor changes correlated with endocannabinoid-dependent long-term potentiation (LTP) at MPP synapses (MPP-LTP) in n-3-H2O and n-3-OH mice. In the former condition, MPP-LTP required group I metabotropic glutamate receptors, 2-arachidonoylglycerol, CB1 receptors, N-type calcium channels and actin filaments assembly. However, TRPV1, NMDA and anandamide were needed in n-3-OH.Altogether, n-3 diet modulates the ECS and potentiates MPP synapses impaired by binge drinking during adolescence.