Ethanol excites synchronized neuronal network activity in the immature hippocampus via an increase in GABA release: Implications for fetal alcohol spectrum disorder

Maternal ethanol (EtOH) exposure results in Fetal Alcohol Spectrum Disorder (FASD). FASD is characterized by neurobehavioral abnormalities such as poor learning and memory, hyperactivity and abnormal social behavior. The cognitive impairments in FASD are mediated by EtOH's effects on neuronal maturation, viability and function. Specifically, the learning and memory deficits seen in children with FASD are attributed, in part, to damage to the hippocampus. Indeed, EtOH affects hippocampal plasticity, kills hippocampal neurons via apoptosis and stunts the growth and maturation of their synapses. However, the mechanism by which EtOH affects the health and development of neurons is not clearly understood, although recent data suggest that EtOH's actions on GABA and NMDA receptors may play an important role in alcohol teratogenicity.;Synchronized neuronal oscillatory activity is crucial for the maturation of neuronal circuits. In the developing hippocampus, these oscillations are called Giant Depolarizing Potentials (GDPs); they are the predominant form of excitatory activity in the immature hippocampus, and are regulated by the excitatory actions of GABA. Neurons are excited rather than inhibited by GABA since the intracellular chloride concentration ([Cl-] i) is high in immature neurons. Consequently, Cl- ions flow outward and depolarize neurons upon GABAA receptor activation. The developmental shift in the function of GABA towards inhibition is achieved by a gradual decrease in [Cl-]i via increases in the expression of the Cl- extruder protein, KCC2. Recent data suggest that excitatory neuronal activity and GABA itself may regulate KCC2 expression.;Given the importance of GABA-mediated GDPs in the maturation of hippocampal circuits and the well-known interactions of EtOH on GABAA receptors. We asked whether EtOH acts as a teratogen by affecting GDP frequency via an increase in GABAA receptor activation. Furthermore, we asked whether an increase in GDP activity by EtOH alters KCC2 expression. We demonstrate that EtOH potently stimulates excitatory network activity in immature neurons by increasing GABA release but not by enhancing GABAA receptor activation. Furthermore, we show that this increase in activity decreases KCC2 expression in vitro but not in vivo. The findings described therein are likely to provide new insights into the pathophysiology of FASD.