UNVEILING THE CONSEQUENCES OF ADOLESCENT ALCOHOL EXPOSURE ON PREFRONTAL CORTEX MATURATION AND RELATED BEHAVIORS

During adolescence, the brain undergoes intense maturation, particularly in the frontal areas. The prefrontal cortex (PFC) is implicated in executive functions, and its immaturity in adolescents is associated with increased impulsivity and heightened vulnerability to drugs. Alcohol is the most consumed drug among adolescents, and its excessive consumption may interfere with the ongoing maturation of frontal brain circuits, leading to long-lasting consequences in PFC structure and function. By using a mouse model of voluntary adolescent binge drinking, we previously reported that AAE leads to severe long-lasting behavioral impairments in both male and female adult mice, characterized by reduced cognitive performances, impaired flexibility, increased alcohol intake, depressive- and anxiety-like behaviors. However, the precise cellular and molecular mechanisms underlying these behavioral impairments are still poorly understood.
In this study, we focus on the consequences of AAE on PFC projection neurons structure and function. Whole cell patch-clamp recordings and biocytin-filling revealed changes in synaptic transmission and morphology of layer V projection neurons. Adolescent drinking mice exhibited increased frequency of spontaneous excitatory postsynaptic current, accompanied by increased NMDA/AMPA ratio and remodeling of NMDA receptor subunit composition toward a higher proportion of NR2B-containing NMDA receptors. Notably, the AAE-induced changes in NMDAR composition and function persisted into adulthood. At the molecular level, translatome analysis of PFC projection neurons by Ribotag-based profiling revealed increased expression of Kdm6B, a lysine demethylase that may contribute to the synaptic transmission defects observed in alcohol-exposed mice.