The objective of this proposal is to explore compromises of the excitatory amino acid system in the rat hippocampal formation caused by prenatal ethanol exposure. An animal model of fetal alcohol (ethanol) syndrome (FAS) will be used to study such changes. Prenatal ethanol exposure exerts profound effects on the CNS, causing dysfunction in numerous physiological and biochemical systems, as well as behavioral alterations. Some of these alterations may occur because of changes in excitatory amino acid receptors. In particular, recent evidence indicates that the N-methyl-D-aspartate (NMDA) receptor may be modified in FAS. The NMDA receptor plays a critical role in processes involved neuronal plasticity, including long-term potentiation (LTP). LTP is an electro- physiological model of learning and memory, and prenatal ethanol exposure disrupts LTP. Thus, learning and memory deficits associated with prenatal exposure may be due to the blockade or compromise of the NMDA receptor. Moreover, evidence is accumulating that this effect of prenatal ethanol exposure is long-lasting. Grease-gap electrophysiological recording methods will be used to characterize the pharmacological properties of both NMDA and non-NMDA receptors in area CAl of the hippocampal formation. An important feature of this technique is that it provides a rapid and accurate means to assess the potency of excitatory amino acid receptor ligands. Using selective agonists and antagonists for the different modulatory sites on excitatory amino acid receptors, with particular emphasis on the NMDA receptor complex, our studies will determine what modulatory site(s) are altered due to prenatal ethanol exposure. In the second part of the proposal, we will study additional areas of the hippocampus, using specific slices for the CA3 and the dentate gyrus regions. We will thus be able to determine whether the induced alterations in excitatory amino acid function occur only in selected regions or in all areas of the hippocampus. The studies proposed here will provide new insights into the molecular mechanisms altered in FAS, and perhaps new data about specific sites on the NMDA receptor-channel complex that are altered by fetal ethanol exposure. The information accumulated from these studies may provide new ideas leading to treatments which will ameliorate FAS disorders.
| Martin, D; Savage, D D; Swartzwelder, H S (1992) Effects of prenatal ethanol exposure on hippocampal ionotropic-quisqualate and kainate receptors. Alcohol Clin Exp Res 16:816-21 |
