Our long-term objectives are to understand the mechanisms of alcohol impairment of neural cell proliferation in the developing brain and how cell-signaling systems mediate the ethanol action. Our general strategy is to focus on a well-characterized neurotransmitter-gated ion channel, GABAA receptor/C1 channel using a newly developed in vitro model of the telencephalic neuroepithelium (TNE) in the central nervous system (CNS). TNE cells can be maintained in division in culture and express ethanol- sensitive GABAA receptor/C1 channels, making the TNE cell culture a useful model of the CNS neuroepithelium to elucidate the cellular and molecular role of cell-signaling systems in ethanol-induced impairment of neural cell proliferation. Our hypothesis is 1) that proliferating TNE cells in culture express functional GABAA receptor/C1 channels; 2) that GABA depolarizes TNE cells via activation of GABAA/C1 channels, and subsequent membrane depolarization activates voltage-gated Ca2+ channels, which trigger an increase in cytoplasmic Ca2+ ([Ca2+]c) levels, and in turn, the elevated [Ca2+]c inhibits DNA synthesis; 3) that ethanol may trigger and potentiate the GABAA receptor/C1 channel signaling pathway and subsequently, inhibit cell proliferation.
Three specific aims of this proposal are to: 1) characterize GABAA receptor/C1 channels in TNE cells; 2) assess the sensitivity of GABAA/C1 channels and TNE cell proliferation to ethanol; and 3) determine how the activation of GABAA/C1 channels and subsequent increase in [Ca2+]c are involved in ethanol-inhibited cell proliferation. The accomplishment of the three aims will advance our understanding of how the GABA- signaling system mediates ethanol action on brain cell proliferation. The pharmacological results of these studies may provide the basis for devising potential therapeutic strategy for treating Fetal Alcohol Syndrome.
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