Early Developmental Ethanol Exposure Disrupts Hippocampal-Dependent Learning via Deregulated NMDA Receptor Function in a Rodent Model of Fetal Alcohol Syndrome

Abstract

Consuming alcohol during pregnancy may lead to a range of lifelong disorders in the resulting offspring known as fetal alcohol spectrum disorders (FASD). The physical and mental impairments are dependent on the developmental timing and resulting blood alcohol concentration. A fetal alcohol syndrome (FAS) rodent model in which a milk/ethanol solution is administered to rat pups across postnatal days (PD) 4-9—a period commensurate to the third trimester in human pregnancy—yields results similar to those seen in individuals with FASD. Behavioral tests given to adult rats are used to assess alcohol’s neurotoxic effects on the developing hippocampus. The context pre-exposure facilitation effect (CPFE) is a form of Pavlovian conditioning in which rats associate a particular context with a footshock. This three-phase task is designed to detect even subtle impairments of hippocampal function following early ethanol exposure, as measured by reduced context-mediated freezing compared to control rats. Alcohol is known to alter NMDA receptor (NMDAR) composition and function across development, a factor that potentially contributes to the deficient learning observed in FAS rats. To investigate this hypothesis, we examine the expression of Arc, an effector immediate early gene (IEG) that is activated downstream of the NMDAR and known to be involved in associative synaptic plasticity and learning. We predict that ethanol-induced NMDAR hypofunction will be detectable by decreased Arc expression in the dorsal and/or ventral sub-region(s) of the hippocampus. Preliminary results indicate administration of an NMDAR partial agonist, D-cycloserine (DCS), prior to initial context exposure facilitates learning in FAS rats, as evidenced by enhanced freezing. Taken together, the data suggest that early developmental ethanol exposure may disrupt NDMAR function, which persists through adulthood, and that pharmacological NMDAR modulation could potentially ameliorate these deficits.