Journal article
Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons
Molecular psychiatry, Vol.28(2), pp.746-758
02/2023
DOI: 10.1038/s41380-022-01818-x
PMCID: PMC9542475
PMID: 36207584
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.
Details
- Title: Subtitle
- Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons
- Creators
- Dina Popova - Rutgers Sexual and Reproductive Health and RightsIsabel Gameiro-Ros - New York, NY USAMark M. Youssef - Piscataway, NJ USAPetronio Zalamea - Piscataway, NJ USAAyeshia D. Morris - Piscataway, NJ USAIya Prytkova - New York, NY USAAzadeh Jadali - Piscataway, NJ USAKelvin Y. Kwan - Piscataway, NJ USAChella Kamarajan - Brooklyn, NY USAJessica E. Salvatore - Piscataway, NJ USAXiaoling Xuei - Indianapolis, IN USADavid B. Chorlian - Brooklyn, NY USABernice Porjesz - Brooklyn, NY USASamuel Kuperman - Iowa City, IA USADanielle M. Dick - Piscataway, NJ USAAlison Goate - New York, NY USAHoward J. Edenberg - Indianapolis, IN USAJay A. Tischfield - Piscataway, NJ USAZhiping P. Pang - Piscataway, NJ USA New Brunswick, NJ USAPaul A. Slesinger - New York, NY USARonald P. Hart - Piscataway, NJ USA Piscataway, NJ USA
- Resource Type
- Journal article
- Publication Details
- Molecular psychiatry, Vol.28(2), pp.746-758
- DOI
- 10.1038/s41380-022-01818-x
- PMID
- 36207584
- PMCID
- PMC9542475
- NLM abbreviation
- Mol Psychiatry
- ISSN
- 1359-4184
- eISSN
- 1476-5578
- Publisher
- Nature Publishing Group UK
- Grant note
- ; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401; U10AA008401 / ;
- Language
- English
- Electronic publication date
- 10/07/2022
- Date published
- 02/2023
- Academic Unit
- Psychiatry
- Record Identifier
- 9984306859402771
Metrics
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