At the cellular level, neurons with the variant KCNJ6 haplotype had a significantly higher density of neurites, accompanied by decreased GIRK2 levels. Physiologically, reduced GIRK2 expression was associated with increased excitability of cells generated from affected individuals both at the level of individual neurons as well as the network (Fig. 1H). Chronic ethanol treatment, however, induced both KCNJ6 mRNA and GIRK2 protein expression, ameliorating differences in neuronal excitability. Moreover, KCNJ6 overexpression alone replicated the effects of ethanol administration on neuronal excitability. These findings are not only reminiscent of the original observation linking subjects with KCNJ6 variants with increased EEG theta oscillations but also supports the hypothesis introduced by Begleiter and Porjesz (Begleiter and Porjesz, 1999), which theorized that inherited neuronal excitability can be associated with a predisposition to developing alcohol dependence.
