Researchers focused on variations within the KCNJ6 gene, which encodes the GIRK2 protein responsible for regulating cell excitability, including responses to alcohol. To investigate this further, the study utilizes a human neuron model system, including individuals with the ERO-associated allelic variant in KCNJ6 and diagnosed alcohol dependence, as well as those without the variant and unaffected by Alcohol Use Disorder (AUD). By examining the transcriptomic and morpho-physiological differences in neurons, the research uncovers initial distinctions in excitability, often accompanied by variations in GIRK2 expression levels. Furthermore, exposure to ethanol is found to induce GIRK2 expression, mitigating differences in neuronal excitability. The study’s findings offer valuable insights into the relationship between genetic variations, neuronal changes, and the risk of AUD, presenting potential avenues for personalized interventions and improved treatment strategies for this complex disorder.
Popova D, Gameiro-Ros I, Youssef MM, Zalamea P, Morris AD, Prytkova I, Jadali A, Kwan KY, Kamarajan C, Salvatore JE, Xuei X, Chorlian DB, Porjesz B, Kuperman S, Dick DM, Goate A, Edenberg HJ, Tischfield JA, Pang ZP, Slesinger PA, Hart RP (2023) Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons. Molecular Psychiatry, 28(2):746-758. PMID: 36207584; PMCID: PMC9542475; DOI: 10.1038/s41380-022-01818-x