Children who suffer cognitive deficits after in utero ethanol intoxication are severely handicapped and struggle to succeed in our complex world. Sadly, there are no treatments to prevent or reverse this injury. Our long- term goal is to rationally identify / test therapies that could protect developing neurocircuits from ethanol injury and preserve cognitive functioning. We have identified a defect in GABA signaling caused when ethanol distorts newly forming synapses. Resulting changes in GABA tone could skew information processing in cognitive neurocircuits causing learning and memory deficits. Synaptic defects could be present even when alcohol-induced neuronal loss does not occur. During a period equivalent to human 3rd trimester brain development, binge-like intoxication in rat pups distorts maturation of GABA miniature postsynaptic currents in medial septum / diagonal band neurons in brain slices. This action seems to be faithfully modeled in primary septal cultures and surprisingly, in cultures, it is largely prevented by finasteride, a drug that blocks formation of 51-reduced neurosteroids. If GABAergic synaptic dysfunction permanently skews inhibitory input to medial septum / diagonal band neurons, then neurocircuit activity essential for cognitive performance could be compromised. In fact, performance in spatial learning and memory tasks is impaired both in children suffering from fetal alcohol exposure and in rats after early postnatal intoxication, suggesting that septal-hippocampal circuits could be dysfunctional. Here we test the hypothesis that 3rd trimester equivalent ethanol intoxication distorts maturation of GABA synapses in the medial septum / diagonal band and disrupts associated cognitive functioning. Whether an intervention such as finasteride can occlude ethanol-induced deficits also will be studied using an established in vivo rodent model of binge ethanol exposure, whole cell electrophysiology, receptor pharmacology and behavioral assessment. If successful, this work could provide a model for testing treatments aimed at offering hope for preventing or limiting cognitive injury.
Children who suffer cognitive deficits from ethanol intoxication during pregnancy can be severely handicapped and struggle to succeed in our complex world. Sadly, there are no treatments to prevent or reverse this injury. The long-term goal of this project is to rationally identify and test therapies that could protect the developing brain from ethanol injury and preserve cognitive functioning in children at risk for fetal alcohol spectrum disorders. ? ? ?
