In a recent study on induced pluripotent stem cell (iPSC)-derived glutamatergic induced human neurons, Popova and colleagues investigated molecular underpinnings of allelic variations in KCNJ6 (Popova et al., 2023). Subjects with and without a haplotype of 22 noncoding or synonymous SNP variations in KCNJ6 were selected from the COGA cell repository, chosen with the presence or absence of AUD diagnosis, respectively, to investigate the cellular, molecular and network mechanisms of these non-coding SNPs. Single-cell RNA sequencing (scRNAseq) identified multiple genes which were differentially expressed between affected and unaffected individuals. Neurons from affected individuals also had significantly lower levels of KCNJ6 mRNA expression. Fluorescence in situ hybridization (FISH) for KCNJ6 mRNA also showed a decrease, consistent with the scRNAseq results. While this conflicts with the in vivo EEG results, cultures of induced excitatory neurons in the absence of neural networks do not recapitulate the full pattern of response in brain. We found that ethanol exposure reversed these effects, demonstrating a mechanism linking ethanol with expression of a gene known to affect excitability.
