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

Synonymous and noncoding single nucleotide polymorphisms (SNPs) in the KCNJ6 gene, encoding G protein-gated inwardly rectifying potassium (GIRK2) channel subunit 2, have been linked with increased electroencephalographic frontal theta event-related oscillations (ERO) in subjects diagnosed with alcoh...

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Published inbioRxiv
Main Authors Popova, Dina, Gameiro-Ros, Isabel, Youssef, Mark M, Petronio Zalamea, Morris, Ayeshia D, Prytkova, Iya, Jadali, Azadeh, Kwan, Kelvin Y, Chella Kamarajan, Salvatore, Jessica E, Edenberg, Howard J, Xuei, Xiaoling, Chorlian, David B, Porjesz, Bernice, Kuperman, Samual, Dick, Danielle M, Goate, Alison, Tischfield, Jay A, Pang, Zhiping P, Slesinger, Paul A, Hart, Ronald P
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 24.05.2022
Subjects
Cytology
EEG
Ethanol
Excitability
Gene expression
Glutamatergic transmission
Inhibitory postsynaptic potentials
Morphogenesis
Neurons
Potassium channels (inwardly-rectifying)
Single-nucleotide polymorphism
Synaptic transmission
Theta rhythms
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Summary:Synonymous and noncoding single nucleotide polymorphisms (SNPs) in the KCNJ6 gene, encoding G protein-gated inwardly rectifying potassium (GIRK2) channel subunit 2, 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. Competing Interest Statement The authors have declared no competing interest. Footnotes * https://doi.org/10.6084/m9.figshare.19798882.v1
DOI:10.1101/2022.05.24.493086