PRENATAL ALCOHOL EXPOSURE ALTERS PREFRONTAL SYNAPTIC PLASTICITY AND SOCIAL BEHAVIOR IN ADOLESCENT MICE

Prenatal alcohol exposure (PAE) leads to a wide range of neurodevelopmental impairments collectively known as fetal alcohol spectrum disorders (FASD). These effects arise from complex and persistent neurochemical alterations during brain development, including disruptions of synaptic plasticity. In this study, we examined whether PAE alters the expression of proteins involved in synaptic plasticity and protein homeostasis in the prefrontal cortex (PFC) of adolescent mice, affects functional cortical connectivity, and how these changes are associated with social behavior. An in vivo model of PAE was established by exposing pregnant C57BL/6 mice to 10% ethanol during early gestation. Offspring were assessed during adolescence for protein expression, cortical functional connectivity, and social behavior. PAE significantly reduced the expression of the neurotrophin BDNF and its receptor TrkB in the PFC, indicating impaired cortical neuroplasticity. These changes were accompanied by disruptions in vesicular trafficking and autophagy pathways, including altered expression of Rab proteins involved in synaptic transport and vesicle recycling, as well as dysregulation of key regulators of protein synthesis and autophagy, such as mTOR, S6, and ULK1. Widefield fluorescence imaging revealed disrupted cortical functional connectivity, reflected by altered correlations in neuronal activity across functionally distinct regions of the dorsal cortical mantle. These molecular and functional alterations were accompanied by reduced sociability. Our findings indicate that PAE induces long-lasting molecular and functional reorganization of the prefrontal cortex, which may underlie the observed social behavioral deficits. These results provide further insight into the neurobiological mechanisms contributing to the pathogenesis of FASD.