@article{3dbab612c9b143e8bad7871ae6da4bf9,
title = "Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons",
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.",
author = "Dina Popova and Isabel Gameiro-Ros and Youssef, {Mark M.} and Petronio Zalamea and Morris, {Ayeshia D.} and Iya Prytkova and Azadeh Jadali and Kwan, {Kelvin Y.} and Chella Kamarajan and Salvatore, {Jessica E.} and Xiaoling Xuei and Chorlian, {David B.} and Bernice Porjesz and Samuel Kuperman and Dick, {Danielle M.} and Alison Goate and Edenberg, {Howard J.} and Tischfield, {Jay A.} and Pang, {Zhiping P.} and Slesinger, {Paul A.} and Hart, {Ronald P.}",
note = "Funding Information: 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{\textquoteright}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{\textquoteright}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{\textquoteright}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). Funding Information: 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{\textquoteright}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{\textquoteright}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{\textquoteright}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). Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2023",
month = feb,
doi = "10.1038/s41380-022-01818-x",
language = "English",
volume = "28",
pages = "746--758",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "2",
}