The adverse effects of prenatal alcohol on the developing central nervous system (CNS) have been well documented and may be permanent in nature, resulting in limited mental capabilities and abnormal behavior. The substrates for these abnormalities are unknown, although cell loss and alterations in neuronal structure have been implicated in studies with animal models. The physiological consequences of these alterations are unknown. In the present proposal a continuation proposal, a culture model system, electrophysiological techniques and a chronic exposure paradigm will be used to identify alcohol induced alterations in the functional properties of CNS neurons that may be the basis for the neurotoxic effects of alcohol in the developing CNS. An identified CNS neuronal type, the cerebellar Purkinje neuron, which is a sensitive and favorable model for alcohol studies in adult animals is the experimental model. the properties to be examined include the postsynaptic mechanisms mediating sensitivity to chemical transmitters and the ionic conductances mediating electrical excitability. Studies completed during the first funding period implicated these mechanisms as target sites of chronic alcohol action in developing Purkinje neurons. Alterations in these properties will be assessed with extracellular and intracellular recording techniques. The site and mechanisms of alcohol action will be determined with voltage-clamp and single channel recording techniques. This approach will provide information at the cellular, membrane and molecular levels and is required to unequivocally identify the sites and mechanisms of alcohol action. Because of the large somatic and dendritic structure of the Purkinje neuron, it will be possible to carry out these studies in both cellular regions. The use of a culture system offers considerable technical advantage and makes it possible to expose the developing neurons to known and stable concentrations of alcohol. This approach minimizes interpretiative problems related to questions of alcohol distribution, actions of metabolic products, nutritional deficits and indirect effects via other sensitive brain regions. The proposed experiments represent a novel and state of the art approach to the study of chronic alcohol actions on CNS neuronal physiology and development. The resulting data should contribute significantly to our understanding of the neurotoxic actions of chronic alcohol on neuronal development and function.
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