In this study, we found that the variant KCNJ6 haplotype affects excitability of neurons (Figs. 3, 4E). In Ca2+ imaging experiments, concomitant with enhanced excitability in neurons from affected individuals following stimulation with glutamate pulses, we observed an overall increase in basal activity of the neuronal population (Fig. 4F). This is reminiscent of the original observation linking KCNJ6 variants with an EEG endophenotype, where Kamarajan et al. observed that individuals with alcohol dependence and the KCNJ6 haplotype had an ERO theta power that varied as a function of the KCNJ6 haplotype in both loss and gain conditions [10]. There is an extensive human literature linking impulsivity to alcohol use problems [64–67]. Impulsivity is elevated in offspring who are at high risk for substance use disorders and may be a reflection of a genetic vulnerability for substance use problems [68]. Excitability in individual neurons and particularly in a culture dish of neurons is several levels of complexity removed from EEG patterns in brain. However, our study points to a mechanistic underpinning of how heritable risk traits are likely to play a role in development of unique physiological response to alcohol in the brain.
