Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons

Molecular Psychiatry volume 28, pages 746–758 (2023)Cite this article

Subjects

Abstract

Synonymous and noncoding single nucleotide polymorphisms (SNPs) in the KCNJ6 gene, encoding G protein-gated inwardly rectifying potassium channel subunit 2 (GIRK2), have been linked with increased electroencephalographic frontal theta event-related oscillations (ERO) in subjects diagnosed with alcohol use disorder (AUD). To identify molecular and cellular mechanisms while retaining the appropriate genetic background, we generated induced excitatory glutamatergic neurons (iN) from iPSCs derived from four AUD-diagnosed subjects with KCNJ6 variants (“Affected: AF”) and four control subjects without variants (“Unaffected: UN”). Neurons were analyzed for changes in gene expression, morphology, excitability and physiological properties. Single-cell RNA sequencing suggests that KCNJ6 AF variant neurons have altered patterns of synaptic transmission and cell projection morphogenesis. Results confirm that AF neurons express lower levels of GIRK2, have greater neurite area, and elevated excitability. Interestingly, exposure to intoxicating concentrations of ethanol induces GIRK2 expression and reverses functional effects in AF neurons. Ectopic overexpression of GIRK2 alone mimics the effect of ethanol to normalize induced excitability. We conclude that KCNJ6 variants decrease GIRK2 expression and increase excitability and that this effect can be minimized or reduced with ethanol.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Experimental design and gene expression analysis.
Fig. 2: Validation of GIRK2 expression and function in human induced neurons.
Fig. 3: Impact of AUD-associated KCNJ6 haplotype on neuronal properties.
Fig. 4: Evaluation of neuronal excitability in human induced neuron populations.
Fig. 5: Ethanol treatment reduced KCNJ6 haplotype differences in iN excitability and GIRK2 expression.
Fig. 6: GIRK2 overexpression mimics ethanol response.

Similar content being viewed by others

References

  1. Verhulst B, Neale MC, Kendler KS. The heritability of alcohol use disorders: a meta-analysis of twin and adoption studies. Psychol Med. 2015;45:1061–72.

    Article  CAS  Google Scholar 

  2. Pollard MS, Tucker JS, Green HD Jr. Changes in adult alcohol use and consequences during the COVID-19 pandemic in the US. JAMA Netw Open. 2020;3:e2022942.

    Article  Google Scholar 

  3. Bouza C, Angeles M, Muñoz A, Amate JM. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 2004;99:811–28.

    Article  Google Scholar 

  4. Heilig M, Egli M. Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol Ther. 2006;111:855–76.

    Article  CAS  Google Scholar 

  5. Skinner MD, Lahmek P, Pham H, Aubin HJ. Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis. PLoS ONE. 2014;9:e87366.

    Article  Google Scholar 

  6. Salvatore JE, Gottesman II, Dick DM. Endophenotypes for alcohol use disorder: an update on the field. Curr Addict Rep. 2015;2:76–90.

    Article  Google Scholar 

  7. Chorlian DB, Rangaswamy M, Manz N, Meyers JL, Kang SJ, Kamarajan C, et al. Genetic correlates of the development of theta event related oscillations in adolescents and young adults. Int J Psychophysiol. 2017;115:24–39.

    Article  Google Scholar 

  8. Kang SJ, Rangaswamy M, Manz N, Wang JC, Wetherill L, Hinrichs T, et al. Family-based genome-wide association study of frontal θ oscillations identifies potassium channel gene KCNJ6. Genes Brain Behav. 2012;11:712–9.

    Article  CAS  Google Scholar 

  9. Clarke TK, Laucht M, Ridinger M, Wodarz N, Rietschel M, Maier W, et al. KCNJ6 is associated with adult alcohol dependence and involved in gene × early life stress interactions in adolescent alcohol drinking. Neuropsychopharmacology 2011;36:1142–8.

    Article  CAS  Google Scholar 

  10. Kamarajan C, Pandey AK, Chorlian DB, Manz N, Stimus AT, Edenberg HJ, et al. A KCNJ6 gene polymorphism modulates theta oscillations during reward processing. Int J Psychophysiol. 2017;115:13–23.

    Article  Google Scholar 

  11. Andrew C, Fein G. Event-related oscillations versus event-related potentials in a P300 task as biomarkers for alcoholism. Alcohol Clin Exp Res. 2010;34:669–80.

    Article  Google Scholar 

  12. Kamarajan C, Rangaswamy M, Tang Y, Chorlian DB, Pandey AK, Roopesh BN, et al. Dysfunctional reward processing in male alcoholics: an ERP study during a gambling task. J Psychiatr Res. 2010;44:576–90.

    Article  Google Scholar 

  13. Glaaser IW, Slesinger PA. Structural insights into GIRK channel function. Int Rev Neurobiol. 2015;123:117–60.

    Article  CAS  Google Scholar 

  14. Luscher C, Slesinger PA. Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease. Nat Rev Neurosci. 2010;11:301–15.

    Article  Google Scholar 

  15. Zhao Y, Gameiro-Ros I, Glaaser IW, Slesinger PA. Advances in targeting GIRK channels in disease. Trends Pharm Sci. 2021;42:203–15.

    Article  CAS  Google Scholar 

  16. Reuveny E, Slesinger PA, Inglese J, Morales JM, Iñiguez-Lluhi JA, Lefkowitz RJ, et al. Activation of the cloned muscarinic potassium channel by G protein beta gamma subunits. Nature 1994;370:143–6.

    Article  CAS  Google Scholar 

  17. Aryal P, Dvir H, Choe S, Slesinger PA. A discrete alcohol pocket involved in GIRK channel activation. Nat Neurosci. 2009;12:988–95.

    Article  CAS  Google Scholar 

  18. Bodhinathan K, Slesinger PA. Alcohol modulation of G-protein-gated inwardly rectifying potassium channels: from binding to therapeutics. Front Physiol. 2014;5:76.

    Article  Google Scholar 

  19. Blednov YA, Stoffel M, Chang SR, Harris RA. Potassium channels as targets for ethanol: studies of G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) null mutant mice. J Pharm Exp Ther. 2001;298:521–30.

    CAS  Google Scholar 

  20. Blednov YA, Stoffel M, Chang SR, Harris RA. GIRK2 deficient mice. Evidence for hyperactivity and reduced anxiety. Physiol Behav. 2001;74:109–17.

    Article  CAS  Google Scholar 

  21. Hill KG, Alva H, Blednov YA, Cunningham CL. Reduced ethanol-induced conditioned taste aversion and conditioned place preference in GIRK2 null mutant mice. Psychopharmacology 2003;169:108–14.

    Article  CAS  Google Scholar 

  22. Lieberman R, Levine ES, Kranzler HR, Abreu C, Covault J. Pilot study of iPS-derived neural cells to examine biologic effects of alcohol on human neurons in vitro. Alcohol Clin Exp Res. 2012;36:1678–87.

    Article  CAS  Google Scholar 

  23. Lieberman R, Kranzler HR, Levine ES, Covault J. Examining the effects of alcohol on GABA(A) receptor mRNA expression and function in neural cultures generated from control and alcohol dependent donor induced pluripotent stem cells. Alcohol. 2018;66:45–53.

    Article  CAS  Google Scholar 

  24. Halikere A, Popova D, Scarnati MS, Hamod A, Swerdel MR, Moore JC, et al. Addiction associated N40D mu-opioid receptor variant modulates synaptic function in human neurons. Mol Psychiatry. 2020;25:1406–19.

    Article  CAS  Google Scholar 

  25. Scarnati MS, Boreland AJ, Joel M, Hart RP, Pang ZP. Differential sensitivity of human neurons carrying mu opioid receptor (MOR) N40D variants in response to ethanol. Alcohol 2020;87:97–109.

    Article  CAS  Google Scholar 

  26. Patzke C, Dai J, Brockmann MM, Sun Z, Fenske P, Rosenmund C, et al. Cannabinoid receptor activation acutely increases synaptic vesicle numbers by activating synapsins in human synapses. Mol Psychiatry. 2021;26:6253–68.

    Article  CAS  Google Scholar 

  27. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 2010;463:1035–41.

    Article  CAS  Google Scholar 

  28. Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, et al. Induction of human neuronal cells by defined transcription factors. Nature 2011;476:220–3.

    Article  CAS  Google Scholar 

  29. Zhang Y, Pak C, Han Y, Ahlenius H, Zhang Z, Chanda S, et al. Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron 2013;78:785–98.

    Article  CAS  Google Scholar 

  30. Lin HC, He Z, Ebert S, Schörnig M, Santel M, Nikolova MT, et al. NGN2 induces diverse neuron types from human pluripotency. Stem Cell Rep. 2021;16:2118–27.

    Article  CAS  Google Scholar 

  31. Bardy C, van den Hurk M, Eames T, Marchand C, Hernandez RV, Kellogg M, et al. Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro. Proc Natl Acad Sci USA. 2015;112:E2725–34.

    Article  CAS  Google Scholar 

  32. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671–5.

    Article  CAS  Google Scholar 

  33. Fantuzzo JA, Robles DA, Mirabella VR, Hart RP, Pang ZP, Zahn JD. Development of a high-throughput arrayed neural circuitry platform using human induced neurons for drug screening applications. Lab Chip. 2020;20:1140–52.

    Article  Google Scholar 

  34. Bates D, Mächler M, Bolker B, Walker S. Fitting linear Mixed-Effects Models Using lme4. J Stat Softw. 2015;67:1–48.

    Article  Google Scholar 

  35. Højsgaard S, Halekoh U, Yan J. The R Package geepack for Generalized Estimating Equations. J Stat Softw. 2005;15:1–11.

    Google Scholar 

  36. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.

    Article  Google Scholar 

  37. Mitchell JM, Nemesh J, Ghosh S, Handsaker RE, Mello CJ, Meyer D, et al. Mapping genetic effects on cellular phenotypes with “cell villages”. bioRxiv. 2020. https://doi.org/10.1101/2020.06.29.174383.

  38. Lesage F, Guillemare E, Fink M, Duprat F, Heurteaux C, Fosset M, et al. Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels. J Biol Chem. 1995;270:28660–7.

    Article  CAS  Google Scholar 

  39. Ang CE, Wernig M. Induced neuronal reprogramming. J Comp Neurol. 2014;522:2877–86.

    Article  CAS  Google Scholar 

  40. Shelby H, Shelby T, Wernig M. Somatic lineage reprogramming. Cold Spring Harb Perspect Biol. 2021;a040808.

  41. Kang HM, Subramaniam M, Targ S, Nguyen M, Maliskova L, McCarthy E, et al. Multiplexed droplet single-cell RNA-sequencing using natural genetic variation. Nat Biotechnol. 2018;36:89–94.

    Article  CAS  Google Scholar 

  42. Marron Fernandez de Velasco E, Zhang L, Baovi NV, Tipps M, Farris S, Xia Z, et al. GIRK2 splice variants and neuronal G protein-gated K(+) channels: implications for channel function and behavior. Sci Rep. 2017;7:1639.

    Article  Google Scholar 

  43. Wydeven N, Marron Fernandez de Velasco E, Du Y, Benneyworth MA, Hearing MC, Fischer RA, et al. Mechanisms underlying the activation of G-protein-gated inwardly rectifying K+ (GIRK) channels by the novel anxiolytic drug, ML297. Proc Natl Acad Sci USA. 2014;111:10755–60.

    Article  CAS  Google Scholar 

  44. Days E, Kaufmann K, Romaine I, Niswender C, Lewis M, Utley T, et al. Discovery and characterization of a selective activator of the G-protein activated inward-rectifying potassium (GIRK) channel. Probe Reports from the NIH Molecular Libraries Program. Bethesda (MD): National Center for Biotechnology Information (US); 2010.

  45. Kang S, Chen X, Gong S, Yu P, Yau S, Su Z, et al. Characteristic analyses of a neural differentiation model from iPSC-derived neuron according to morphology, physiology, and global gene expression pattern. Sci Rep. 2017;7:12233.

    Article  Google Scholar 

  46. Chen TW, Wardill TJ, Sun Y, Pulver SR, Renninger SL, Baohan A, et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 2013;499:295–300.

    Article  CAS  Google Scholar 

  47. Steri M, Idda ML, Whalen MB, Orrù V. Genetic variants in mRNA untranslated regions. Wiley Interdiscip Rev RNA. 2018;9:e1474.

    Article  Google Scholar 

  48. Wang D, Liu S, Warrell J, Won H, Shi X, Navarro FCP, et al. Comprehensive functional genomic resource and integrative model for the human brain. Science 2018. https://doi.org/10.1126/science.aat8464.

  49. Nunez YO, Mayfield RD. Understanding alcoholism through microRNA signatures in brains of human alcoholics. Front Genet. 2012;3:43.

    Article  CAS  Google Scholar 

  50. Wehrspaun C, Ponting C, Marques A. Brain-expressed 3′UTR extensions strengthen miRNA cross-talk between ion channel/transporter encoding mRNAs. Fronti Genet. 2014. https://doi.org/10.3389/fgene.2014.00041.

  51. Suda S, Nibuya M, Suda H, Takamatsu K, Miyazaki T, Nomura S, et al. Potassium channel mRNAs with AU-rich elements and brain-specific expression. Biochem Biophys Res Commun. 2002;291:1265–71.

    Article  CAS  Google Scholar 

  52. Brenner E, Tiwari GR, Kapoor M, Liu Y, Brock A, Mayfield RD. Single cell transcriptome profiling of the human alcohol-dependent brain. Hum Mol Genet. 2020;29:1144–53.

    Article  CAS  Google Scholar 

  53. Bodhinathan K, Slesinger PA. Molecular mechanism underlying ethanol activation of G-protein-gated inwardly rectifying potassium channels. Proc Natl Acad Sci USA. 2013;110:18309–14.

    Article  CAS  Google Scholar 

  54. Sathyan P, Golden HB, Miranda RC. Competing interactions between micro-RNAs determine neural progenitor survival and proliferation after ethanol exposure: evidence from an ex vivo model of the fetal cerebral cortical neuroepithelium. J Neurosci. 2007;27:8546–57.

    Article  CAS  Google Scholar 

  55. Pietrzykowski AZ, Friesen RM, Martin GE, Puig SI, Nowak CL, Wynne PM, et al. Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol. Neuron 2008;59:274–87.

    Article  CAS  Google Scholar 

  56. Lewohl JM, Nunez YO, Dodd PR, Tiwari GR, Harris RA, Mayfield RD. Up-regulation of microRNAs in brain of human alcoholics. Alcohol Clin Exp Res. 2011;35:1928–37.

    Article  CAS  Google Scholar 

  57. Osterndorff-Kahanek EA, Tiwari GR, Lopez MF, Becker HC, Harris RA, Mayfield RD. Long-term ethanol exposure: Temporal pattern of microRNA expression and associated mRNA gene networks in mouse brain. PLoS ONE. 2018;13:e0190841.

    Article  Google Scholar 

  58. Lim Y, Beane-Ebel JE, Tanaka Y, Ning B, Husted CR, Henderson DC, et al. Exploration of alcohol use disorder-associated brain miRNA-mRNA regulatory networks. Transl Psychiatry. 2021;11:504.

    Article  CAS  Google Scholar 

  59. Zhu S, Wu J, Hu J. Non-coding RNA in alcohol use disorder by affecting synaptic plasticity. Exp Brain Res. 2022;240:365–79.

    Article  CAS  Google Scholar 

  60. Best TK, Siarey RJ, Galdzicki Z. Ts65Dn, a mouse model of Down syndrome, exhibits increased GABAB-induced potassium current. J Neurophysiol. 2007;97:892–900.

    Article  CAS  Google Scholar 

  61. Harashima C, Jacobowitz DM, Witta J, Borke RC, Best TK, Siarey RJ, et al. Abnormal expression of the G-protein-activated inwardly rectifying potassium channel 2 (GIRK2) in hippocampus, frontal cortex, and substantia nigra of Ts65Dn mouse: a model of Down syndrome. J Comp Neurol. 2006;494:815–33.

    Article  CAS  Google Scholar 

  62. Reeves RH, Irving NG, Moran TH, Wohn A, Kitt C, Sisodia SS, et al. A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat Genet. 1995;11:177–84.

    Article  CAS  Google Scholar 

  63. Kleschevnikov AM, Yu J, Kim J, Lysenko LV, Zeng Z, Yu YE, et al. Evidence that increased Kcnj6 gene dose is necessary for deficits in behavior and dentate gyrus synaptic plasticity in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis. 2017;103:1–10.

    Article  CAS  Google Scholar 

  64. Congdon E, Canli T. The endophenotype of impulsivity: reaching consilience through behavioral, genetic, and neuroimaging approaches. Behav Cogn Neurosci Rev. 2005;4:262–81.

    Article  Google Scholar 

  65. Dick DM, Smith G, Olausson P, Mitchell SH, Leeman RF, O’Malley SS, et al. Understanding the construct of impulsivity and its relationship to alcohol use disorders. Addict Biol. 2010;15:217–26.

    Article  Google Scholar 

  66. Sher KJ, Trull TJ. Personality and disinhibitory psychopathology: alcoholism and antisocial personality disorder. J Abnorm Psychol. 1994;103:92–102.

    Article  CAS  Google Scholar 

  67. Verdejo-García A, Lawrence AJ, Clark L. Impulsivity as a vulnerability marker for substance-use disorders: review of findings from high-risk research, problem gamblers and genetic association studies. Neurosci Biobehav Rev. 2008;32:777–810.

    Article  Google Scholar 

  68. Polich J, Bloom FE. P300, alcoholism heritability, and stimulus modality. Alcohol. 1999;17:149–56.

    Article  CAS  Google Scholar 

  69. Cáceres A, Banker GA, Binder L. Immunocytochemical localization of tubulin and microtubule-associated protein 2 during the development of hippocampal neurons in culture. J Neurosci. 1986;6:714–22.

    Article  Google Scholar 

  70. Ma F, Xu J, Liu Y, Popova D, Youssef MM, Hart RP, et al. The amyloid precursor protein modulates the position and length of the axon initial segment offering a new perspective on Alzheimer’s disease genetics. bioRxiv. 2022. https://doi.org/10.1101/2022.01.23.477413.

Download references

Acknowledgements

The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators BP, V. Hesselbrock, T. Foroud; Scientific Director, A. Agrawal; Translational Director, DMD, includes eleven different centers: University of Connecticut (V. Hesselbrock); Indiana University (HJE, T. Foroud, Y. Liu, M. Plawecki); University of Iowa Carver College of Medicine (SK, J. Kramer); SUNY Downstate Health Sciences University (BP, J. Meyers, CK, A. Pandey); Washington University in St. Louis (L. Bierut, J. Rice, K. Bucholz, A. Agrawal); University of California at San Diego (M. Schuckit); Rutgers University (JAT, RPH, JES); The Children’s Hospital of Philadelphia, University of Pennsylvania (L. Almasy); Virginia Commonwealth University (DMD); Icahn School of Medicine at Mount Sinai (A. AG, PAS); and Howard University (D. Scott). Other COGA collaborators include: L. Bauer (University of Connecticut); J. Nurnberger Jr., L. Wetherill, XX, D. Lai, S. O’Connor, (Indiana University); G. Chan (University of Iowa; University of Connecticut); DBC, J. Zhang, P. Barr, S. Kinreich, G. Pandey (SUNY Downstate); N. Mullins (Icahn School of Medicine at Mount Sinai); A. Anokhin, S. Hartz, E. Johnson, V. McCutcheon, S. Saccone (Washington University); J. Moore, ZPP, S. Kuo (Rutgers University); A. Merikangas (The Children’s Hospital of Philadelphia and University of Pennsylvania); F. Aliev (Virginia Commonwealth University); H. Chin and A. Parsian are the NIAAA Staff Collaborators. We continue to be inspired by our memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, P. Michael Conneally, Raymond Crowe, and Wendy Reich, for their critical contributions. This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug abuse (NIDA).

Author information

Authors and Affiliations

  1. Human Genetics Institute, Rutgers University, Piscataway, NJ, USA

    Dina Popova, Petronio Zalamea, Jay A. Tischfield, Zhiping P. Pang & Ronald P. Hart

  2. Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Isabel Gameiro-Ros, Iya Prytkova & Paul A. Slesinger

  3. Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, NJ, USA

    Mark M. Youssef, Azadeh Jadali, Kelvin Y. Kwan & Ronald P. Hart

  4. Joint Program in Toxicology, Rutgers University, Piscataway, NJ, USA

    Ayeshia D. Morris

  5. Dept. of Psychiatry & Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA

    Chella Kamarajan, David B. Chorlian & Bernice Porjesz

  6. Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA

    Jessica E. Salvatore

  7. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    Xiaoling Xuei

  8. Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA

    Samuel Kuperman

  9. Rutgers Addiction Research Center, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA

    Danielle M. Dick

  10. Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Alison Goate

  11. Department of Biochemistry and Molecular Biology, Indiana Univ School of Medicine, Indianapolis, IN, USA

    Howard J. Edenberg

  12. Child Health Institute, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA

    Zhiping P. Pang

Authors
  1. Dina Popova
    View author publications

    Search author on:PubMed Google Scholar

  2. Isabel Gameiro-Ros
    View author publications

    Search author on:PubMed Google Scholar

  3. Mark M. Youssef
    View author publications

    Search author on:PubMed Google Scholar

  4. Petronio Zalamea
    View author publications

    Search author on:PubMed Google Scholar

  5. Ayeshia D. Morris
    View author publications

    Search author on:PubMed Google Scholar

  6. Iya Prytkova
    View author publications

    Search author on:PubMed Google Scholar

  7. Azadeh Jadali
    View author publications

    Search author on:PubMed Google Scholar

  8. Kelvin Y. Kwan
    View author publications

    Search author on:PubMed Google Scholar

  9. Chella Kamarajan
    View author publications

    Search author on:PubMed Google Scholar

  10. Jessica E. Salvatore
    View author publications

    Search author on:PubMed Google Scholar

  11. Xiaoling Xuei
    View author publications

    Search author on:PubMed Google Scholar

  12. David B. Chorlian
    View author publications

    Search author on:PubMed Google Scholar

  13. Bernice Porjesz
    View author publications

    Search author on:PubMed Google Scholar

  14. Samuel Kuperman
    View author publications

    Search author on:PubMed Google Scholar

  15. Danielle M. Dick
    View author publications

    Search author on:PubMed Google Scholar

  16. Alison Goate
    View author publications

    Search author on:PubMed Google Scholar

  17. Howard J. Edenberg
    View author publications

    Search author on:PubMed Google Scholar

  18. Jay A. Tischfield
    View author publications

    Search author on:PubMed Google Scholar

  19. Zhiping P. Pang
    View author publications

    Search author on:PubMed Google Scholar

  20. Paul A. Slesinger
    View author publications

    Search author on:PubMed Google Scholar

  21. Ronald P. Hart
    View author publications

    Search author on:PubMed Google Scholar

Contributions

DP, IG-R, JAT, ZPP, PAS, and RPH conceived the project. DP, IG-R, MMY, PZ, ADM, IP, AJ, KYK, and RPH performed experiments. DP, IG-R, IP, JES, PAS, and RPH performed statistical analyses. CK, XX DBC, BP, SK, DMD, AG, HJE, and JAT characterized and identified subjects for analysis and provided critical feedback throughout the project. DP, IG-R, PAS, and RPH prepared the paper with critical evaluation from JES, HJE, JAT, and ZPP.

Corresponding author

Correspondence to Ronald P. Hart.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Popova, D., Gameiro-Ros, I., Youssef, M.M. et al. Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons. Mol Psychiatry 28, 746–758 (2023). https://doi.org/10.1038/s41380-022-01818-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41380-022-01818-x

This article is cited by

Search

Advanced search

Quick links