Long term learning disabilities have been described in children exposed to ethanol in utero. The hippocampal formation, an area of the brain 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. Morphologic, neurochemical, electrophysiological and behavioral evidence indicate the presence of a functional deficit in the hippocampal formation of animals exposed to ethanol prenatally. At present, little is known about which hippocampal neurochemical parameters are altered or how these alterations might lead to a net decrease in hippocampal neurotransmission. The long-term objective of this project is to identify what prenatal ethanol-induced neurochemical alterations occur in hippocampal formation and what relationships may exist between these alterations and some electrophysiological and behavioral consequences of prenatal ethanol exposure.
The specific aims of our competing renewal grant application are: 1) We will examine the effect of prenatal ethanol exposure on the N-methyl- D-aspartate (NMDA) and quisqualate (QUIS) subtypes of hippocampal glutamate receptors, using receptor autoradiography techniques. We have previously reported reductions in total glutamate and kainate-sensitive glutamate binding in fetal alcohol rat hippocampal formation. The NMDA and QUIS studies will complete our radiohistochemical investigation of glutamate receptor binding in fetal alcohol rat hippocampal formation. 2) We will examine the interaction between the NMDA receptor and the phencyclidine (PCP) receptor along with the allosteric regulation of these binding sites by glycine. Our preliminary results indicate a decrease in NMDA receptors in fetal alcohol hippocampus. This reduction could affect how the NMDA/PCP system activates a cation-selective channel thought to play an important role in hippocampal neuronal plasticity. 3) We will examine basal and QUIS receptor-mediated activation of phosphoinositide (PI) hydrolysis in fetal alcohol hippocampal formation. The accumulation of radiolabelled inositol phosphate (3H-IP1) in hippocampal slices will be measured. PI hydrolysis is an important step for signal amplification by some neurotransmitters such as glutamate. Examination of basal and QUIS-stimulated PI hydrolysis will allow us to determine whether this receptor-transduction system is affected by fetal alcohol exposure. 4) We will examine the effect of fetal ethanol exposure on protein kinase C (PKC) mediated phosphorylation of hippocampal F1 protein. A relatively selective phosphorylation of F1 protein has been associated with the generation of long term potentiation, an electrophysiological phenomenon thought to mediate the memory consolidation function of hippocampal formation. We will also examine the amount and distribution of 3H-phorbol dibutyrate binding to PKC in various brain regions of control and fetal alcohol rats using radiohistochemical techniques. 5) We will examine the effect of fetal ethanol exposure on the number of dentate granule and hippocampal pyramidal neurons. One explanation for a reduction in the number of glutamate receptor binding sites and hippocampal mossy fiber zinc may be a decrease in the number of hippocampal formation neurons containing glutamate receptors and zinc. We will measure cell density in the stratum granulosum of dentate gyrus and stratum pyramidale of hippocampal CA3, CA1 and subiculum in control and fetal alcohol rats.
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