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Chunk #27 — Discussion

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Examining the effects of alcohol on GABA receptor mRNA expression and function in neural cultures generated from control and alcohol dependent donor induced pluripotent stem cells.
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Downregulation of the GABRA1 gene following alcohol exposure has often been observed in adult rodent models (Mhatre and Ticku 1992, Devaud et al. 1995, Kumar et al. 2009). In contrast, we found increased expression of GABRA1 following 21-day alcohol exposure in our human neural cell model. This difference in findings may be related to the difference in age and maturity of our neural cultures compared with adult rodent cells. Comparisons between iPSC-derived neural cells and human brain showed that the transcriptome profile of iPSC-derived neural cultures most closely resembles that of first trimester fetal brain tissue (Brennand et al. 2015), suggesting that iPSC-derived neural cultures may be a particularly suitable model to examine the toxic effects of prenatal alcohol consumption related to fetal alcohol spectrum disorder. Rodent models of fetal alcohol syndrome have reported excessive activation of GABA synaptic transmission (Ikonomidou et al. 2000) and regulation of GABAA receptor subunits including a downregulation of α5 expression in brain (Toso et al. 2006), upregulation of the β2/3 subunit in the hippocampus (Iqbal et al. 2004) and upregulation of δ expression and