Prenatal Alcohol Exposure shapes cortical development and alters social behaviors in adolescent mice

Background: Prenatal alcohol exposure (PAE) leads to neurodevelopmental disabilities and social skill deficits, classified as fetal alcohol spectrum disorders (FASD). Hence, we investigated whether PAE a=ects glutamatergic synaptic composition in the prefrontal cortex (PFC) and cortical networks dynamics, as well as its impact on social behaviors in adolescent mice. Methods: We generated an in vivo model of PAE, by exposing C57Bl/6 pregnant mice to 10% EtOH during the first 10 days of gestation. O=springs were analyzed during adolescence for protein expression in the PFC, functional cortical connectivity and social behaviors. Results: In the synaptic fraction of the PFC, PAE significantly altered the subunit composition of AMPA receptors toward GluA2-containing receptors and increased NMDA receptors, associated with enhanced expression of relative sca=olding proteins. These changes were paralleled by altered expression of Rab proteins, regulators of synaptic tra=icking and vesicular recycling. Moreover, widefield fluorescence microscopy unraveled decreased excitability in visual and retrosplenial areas, as well as in secondary motor area, which is interconnected with the PFC. In addition, PAE o=spring shows reduced social memory and sociability, without a=ecting locomotor activity and hedonic tone. Conclusions: These findings suggest that PAE shapes brain development and social behaviors through enduring reorganization of glutamatergic synapsis in the PFC and remodeling of cortical network, paving the way for potential pharmacological targets for FASD.