Prenatal Alcohol Exposure Dysregulates the Glutamatergic Synapse Composition in the Prefrontal Cortex of Adolescent Mice
Beatrice Rizzi, Francesca Mottarlini, Valentina Scianaro, Fabio Fumagalli, Guido Mannaioni, Lucia Caffino, Elisabetta GeraceIntroduction/Objective:
Prenatal alcohol exposure (PAE) is a leading preventable cause of neurodevelopmental disorders collectively known as fetal alcohol spectrum disorders (FASD). Since glutamatergic signaling is essential for brain development and synaptic plasticity, we investigated whether PAE alters the molecular composition of the glutamatergic synapses in the prefrontal cortex (PFC) in adolescent mice.
Methods:
To model PAE, pregnant C57Bl/6J mice were given 10% ethanol (EtOH) voluntarily during the first 10 days of gestation (GD 0-10), corresponding to the first trimester of human pregnancy. The postsynaptic expression of AMPA and NMDA receptor subunits and related scaffolding proteins was then analyzed in the PFC of PAE adolescent offspring by Western blotting.
Results:
PAE significantly altered the molecular composition of glutamatergic postsynaptic densities, reducing GluA1 and increasing GluA2 -containing AMPA receptors, together with increased GluN1/GluN2A NMDA receptor expression, altering synaptic scaffolding proteins, and enhancing αCaMKII phosphorylation.
Discussion:
These findings indicate that PAE alters the subunit composition, stabilization, and localization of NMDA and AMPA receptors, inducing persistent molecular remodeling of excitatory synapses in the adolescent PFC. The reorganization of the cortical synapses may potentially disrupt synaptic plasticity and cortical network maturation.
Conclusions:
These persistent alterations may help explain impaired synaptic plasticity and cognitive and behavioral deficits previously observed in FASD, including impairments in recognition memory, exploratory behavior, and reward processing.