MODERATE ETHANOL PRENATALLY ON NMDA PHOSPHORYLATION

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Studies in our laboratory and by others indicate that prenatal and early postnatal ethanol exposure results in a significant reduction of NMDA receptor function and number. NMDA receptors are linked with important aspects of brain development and learning and memory. Ethanol-related deficits in NMDA function, therefore, may be of key importance not only in the severe cognitive and behavioral deficiencies of fetal alcohol syndrome (FAS) but also in alcohol-related neurodevelopmental disorders (ARND) typically expressed as behavioral symptoms associated with fetal alcohol effects (FAE). We have recently found that decreases in NMDA receptor function resulting from prenatal ethanol exposure in rats are accompanied by reductions in some, but not all, of the subunits comprising the NMDA receptor complex. NMDAR2A and NMDAR2B subunits are significantly reduced, while the NMDAR1 subunit is unaffected. Studies conducted thus far have examined the effects of high doses of ethanol prenatally and postnatally on NMDA receptor function and subunit levels. Studies proposed in specific aims 1 through 4 are designed to determine the dose-response relationships of prenatal ethanol treatment on 1) functional measures of NMDA receptor activation using fura-2 loaded dissociated neurons and H-MK801 binding, 2) NMDAR1 and NMDAR2 subunit protein (Western blot analysis) and messenger RNA levels (RNase protection assay), and 3) changes in NMDA receptor subunit composition as measured by immunoprecipitation studies. Specific aim 4 will examine the relationship(s) of NMDA receptor subunit changes with changes in subunit phosphorylation. The overall hypothesis of this proposal is that prenatal ethanol exposure, even at modest concentrations, will result in demonstrable deficits in the function of NMDA receptors. We expect the magnitude of the deficits to be dose-related. It is hypothesized further that ethanol's actions in this regard may be linked with abnormalities of NMDA receptor phosphorylation.