While it is well known that prenatal ethanol (ETOH) exposure has detrimental effects on the developing CNS, there are still numerous questions regarding the mechanisms underlying the CNS damage observed. The effects of ETOH on the glutamate/NMDA receptor (NMDAR) are well established. ETOH-induced alterations in NMDAR function during development causes hippocampal damage by at least two mechanisms; reduced NMDAR function during the presence of ETOH (via apoptosis) and enhanced NMDAR function during ETOH withdrawal (via excitotoxicity). Which of these mechanisms predominates may be age- dependent with suppression of NMDAR activity being more damaging at earlier developmental stages and overexcitation during ETOH WD being a more dominant component in older cultures. Polyamines are ubiquitous compounds that also play an important trophic role during CNS development and one of the mechanisms by which polyamines work is by potentiation of the NMDAR. Since hippocampal NMDAR subtypes and their response to polyamines change during the first neonatal weeks in rats, the timing when ETOH exposure occurs may have significant influences on response to polyamines, NMDAR and outcome. These hypotheses can be tested directly in vitro using the organotypic cell culture model and comparing cultures obtained from neonatal rats at PND 2 versus PND 8.
The specific aims are 1) to examine how developmental age affects the response to ETOH as measured by cell damage in our in vitro organotyplc hippocampal model; 2) to examine how developmental age and ETOH exposure interact with polyamines as measured by cell damage in the in vitro hippocampal model and 3) To assess whether in vivo ETOH exposure correlates with the findings from in vitro exposure. The model proposed in this application will provide an innovative and novel approach for using hippocampal organotypic cell cultures to address specific developmental questions related to ETOH's effects and to assess the predictive validity of the model to predict in vivo results. With these findings, it may also be possible to gain a better understanding of some of the mechanisms underlying neonatal ETOH exposure and the role of polyamines that will provide grounds for pharmacological interventions that will reduce some of ETOH effects.
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