Abnormal morphology of nerve cells occurs in mental retardation of varied causes; the most common cause, however, may be fetal alcohol exposure. Overall 8% of all children with mild retardation may suffer fetal alcohol effects. The fetal alcohol syndrome (approximately 1/600 births) includes craniofacial abnormalities, limb defects, and moderate to severe mental retardation; however, significant learning and behavioral deficits may occur in the absence of malformations, microcephaly, and mental retardation. The economic impact is considerable and includes not only intensive care for the small-for-dates newborns and surgery to correct defects, but also institutional care. Current questions include whether low concentrations of alcohol harm the developing brain and whether recovery from fetal exposure is possible. This proposal will utilize a tissue culture model of neuronal development to investigate several clinically relevant questions as well as the mechanisms by which neuronal development is disturbed. The outgrowth of two classes of processes, axons and dendrites, determines the morphology of nerve cells. Akons form interconnections essential to the function of the nervous system. Dendrites, by serving as the major target site for input of information from other nerve cells, mediate important integrative functions, including learning and memory. Rat sympathetic neurons can be maintained for weeks in culture bearing only axons. By manipulation of media components (serum or extracellular matrix proteins) or by addition of their normal companion glia, Schwann cells, the formation of dendrites can be induced. Immunocytochemistry, video/time-lapse photography, and computerized morphometry will be utilized to analyze the effects of alcohol on both axonal and dendritic development in cultures treated chronically with low concentrations of alcohol or with a single application of a high concentration. The direct effect of alcohol on the motility and cytoskeletal organization of growth cones of both axons and dendrites will be analyzed. The hypothesis will be tested that alcohol may alter axonal and dendritic development by perturbating cell surface or extracellular matrix molecules resulting in changes in axonal and dendritic growth cone morphology and function. The prdposed experiments will contribute new information not only concerning clinically related questions on fetal alcohol exposure and the possible mechanisms by which alcohol may act, but also how a neuron normally develops and maintains its distinctive morphblogy.
