Long-term learning disabilities have been described in children exposed to ethanol in utero. The hippocampal formation, a brain region involved with memory consolidation, is quite sensitive to the effects of prenatal ethanol exposure both in humans and animal models of in utero ethanol exposure. We have observed deficits in hippocampal glutamate neurotransmission in rat offspring whose mothers consumed moderate quantities of ethanol throughout gestation. As the hippocampal glutamatergic system is thought to participate in memory formation, this defect may contribute to subtle learning deficits in offspring whose mothers consumed moderate amounts of ethanol during gestation. The objectives of this proposal are to obtain a better understanding of prenatal ethanol-induced hippocampal glutamate receptor deficits and to initiate studies of environmental factors that affect the expression of these teratogenic effects.
The specific aims are to: 1. Examine the effects of prenatal ethanol exposure on neurochemical markers of glutamate neurotransmission and mossy fiber zinc in developing offspring. We will determine what neurochemical teratology is expressed during development, which alterations persist into young adulthood and whether the pattern of alterations suggest developmental delay or permanent deficits. 2. Examine the impact of rat dam age on prenatal ethanol exposure-induced neurochemical deficits. We will determine which rat dam age produces offspring with the greatest degree of neurochemical teratology. 3. Examine the effect of varied periods of prenatal ethanol exposure on hippocampal neurochemistry. We will determine the minimal number of days of prenatal ethanol exposure that produce: 1) the smallest statistically significant changes and 2) the maximal changes in each neurochemical parameter. 4. Examine the effect of maternal blood ethanol concentration (BEC) on hippocampal neurochemistry. We will determine the lowest maternal BEC that produces significant neurochemical alterations and whether maximal changes in these parameters occur within the BEC range studied. These studies will provide a clearer picture of developmental expression of neurochemical defects in offspring, the impact of maternal age, ethanol dose and timing during fetal development on the expression of these neurochemical defects and a more detailed understanding of the nature of these neurochemical alterations. Finally, this data will provide information to facilitate the design of future studies of other environmental and genetic factors along with clues that may lead to studies designed to directly test hypotheses about the mechanism(s) of prenatal ethanol action on developing hippocampal formation.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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Biochemistry, Physiology and Medicine Subcommittee (ALCB)
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University of New Mexico
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Savage, Daniel D; Becher, Matthew; de la Torre, Alejandro J et al. (2002) Dose-dependent effects of prenatal ethanol exposure on synaptic plasticity and learning in mature offspring. Alcohol Clin Exp Res 26:1752-8
Weeber, E J; Savage, D D; Sutherland, R J et al. (2001) Fear conditioning-induced alterations of phospholipase C-beta1a protein level and enzyme activity in rat hippocampal formation and medial frontal cortex. Neurobiol Learn Mem 76:151-82
Savage, D D; Galindo, R; Queen, S A et al. (2001) Characterization of electrically evoked [3H]-D-aspartate release from hippocampal slices. Neurochem Int 38:255-67
Costa, E T; Olivera, D S; Meyer, D A et al. (2000) Fetal alcohol exposure alters neurosteroid modulation of hippocampal N-methyl-D-aspartate receptors. J Biol Chem 275:38268-74
Costa, E T; Savage, D D; Valenzuela, C F (2000) A review of the effects of prenatal or early postnatal ethanol exposure on brain ligand-gated ion channels. Alcohol Clin Exp Res 24:706-15
Savage, D D; Cruz, L L; Duran, L M et al. (1998) Prenatal ethanol exposure diminishes activity-dependent potentiation of amino acid neurotransmitter release in adult rat offspring. Alcohol Clin Exp Res 22:1771-7
Perrone-Bizzozero, N I; Isaacson, T V; Keidan, G M et al. (1998) Prenatal ethanol exposure decreases GAP-43 phosphorylation and protein kinase C activity in the hippocampus of adult rat offspring. J Neurochem 71:2104-11
Allan, A M; Wu, H; Paxton, L L et al. (1998) Prenatal ethanol exposure alters the modulation of the gamma-aminobutyric acidA1 receptor-gated chloride ion channel in adult rat offspring. J Pharmacol Exp Ther 284:250-7
Allan, A M; Weeber, E J; Savage, D D et al. (1997) Effects of prenatal ethanol exposure on phospholipase C-beta 1 and phospholipase A2 in hippocampus and medial frontal cortex of adult rat offspring. Alcohol Clin Exp Res 21:1534-41
Carpenter, S P; Savage, D D; Schultz, E D et al. (1997) Ethanol-mediated transplacental induction of CYP2E1 in fetal rat liver. J Pharmacol Exp Ther 282:1028-36

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