Alcohol consumption during pregnancy has a profound effect on the developing fetus. Most notable is fetal alcohol syndrome (FAS), an affliction that includes craniofacial abnormalities, reduced brain mass, and a variety of sensory, motor, learning, and attentional deficits. The neurotoxic effects of alcohol on fetal brain development have been recognized for many years but the underlying mechanisms remain a mystery. This problem can be attributed to the lack of an adequate animal model in which the effects of alcohol can be experimentally assessed and analyzed. Our plan is to utilize a rodent model of visual system development to gain insight into the underlying mechanisms. The developing connections between the retina and its thalamic target, the lateral geniculate nucleus (LGN), experiences substantial remodeling during the first three weeks of life. Many of the developmental changes have been characterized on a structural and functional level and depend critically on neural activity during perinatal development. The long-term goal is to assess whether alcohol exposure during different stages of gestation affects the form and function of the developing retinogeniculate pathway. It is our assertion that early alcohol exposure will disturb early activity and prevent the normal development of adult-like connections. This will afford us an opportunity to examine on a cellular and systems level the manner in which early alcohol affects brain development. We shall administer daily doses of ethanol via gastric intubation to pregnant females during the first (E1-E10) or second (E11-21 ) trimester human equivalent of gestation. Control animals will be administered an equivalent volume of a maltose dextrin solution. We shall examine the structural and functional integrity of LGN at the following postnatal (P) ages: P2, P7, P14, P21 and P30. This is the most labile period of retinogeniculate development whereby retinal inputs stabilize to form adult-like patterns of connections and LGN cells take on adult like properties. Using anterograde labeling techniques, we shall examine the pattern of retinal projections in LGN to see if alcohol exposure disrupts the nature and time course of retinogeniculate axon segregation. Using a battery of monoclonal antibodies directed toward ligand gated receptors (AMPA, NMDAR-1, GABA), voltage gated ion channels (L-type Ca channels) Ca dependent signaling events (CaM CREB and CaM kinase II), and neurofilament proteins (SMI-32), we shall assess the structural integrity of developing LGN cells. Using in vitro recording techniques on thalamic slices we shall examine the functional state of LGN cells by exploring how ethanol affects the electrophysiological properties and synaptic responses of LGN cells.
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