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<p>Alterations of GABA<sub>A</sub> receptors (GABA<sub>A</sub>Rs) following chronic alcohol are thought to be related to deficits in GABAergic signaling in individuals with alcohol use disorder (AUD). Whether those modifications affect the function of synaptic GABA<sub>A</sub>Rs is not clear, as the electrophysiological characterization of native synaptic receptors from AUD individuals had not been done. To obtain this information, we microtransplanted synaptic membranes from postmortem dorsolateral prefrontal cortex (DLPFC) samples of AUD and non-AUD subjects to determine functional traits of GABA<sub>A</sub>Rs. To follow the path from transcription to function of potential changes of GABA<sub>A</sub>Rs in AUD, GABA<sub>A</sub>Rs currents and GABA pEC<sub>50</sub> values were integrated with RNA-Seq and label-free proteomics datasets of bulk tissue and isolated synaptosomes from the same subjects. Our results outline significant reconfigurations in transcriptomic organization of GABA<sub>A</sub>Rs in AUD, higher levels of <i>GABRG1</i> and significant decrease of mitochondrial transcripts in AUD individuals. Notably, transcriptional differences were gradually lost as the analysis moved from transcription to protein and function within our cohort. This suggests post-translational buffering in AUD resulting in unchanged GABA receptor synaptic activity. Our novel findings establish a proof of concept for reactivating AUD post-synaptic receptors and integrating this information with multiple levels of multi-omic analyses, as well as outline hypothesis-generating insights into this multifaceted disease.</p>

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Multi-omics and electrophysiological examination of GABAA receptors in the dorsolateral prefrontal cortex of humans with alcohol use disorder

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月11日

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  • J. Granchi,
  • B. Salameh,
  • B. Miller,
  • P. Scaduto,
  • W. K. Russell,
  • T. D. Meyer,
  • A. L. Teixeira,
  • G. R. Fries,
  • L. Stertz,
  • C. Walss-Bass,
  • A. Limon

摘要

Alterations of GABAA receptors (GABAARs) following chronic alcohol are thought to be related to deficits in GABAergic signaling in individuals with alcohol use disorder (AUD). Whether those modifications affect the function of synaptic GABAARs is not clear, as the electrophysiological characterization of native synaptic receptors from AUD individuals had not been done. To obtain this information, we microtransplanted synaptic membranes from postmortem dorsolateral prefrontal cortex (DLPFC) samples of AUD and non-AUD subjects to determine functional traits of GABAARs. To follow the path from transcription to function of potential changes of GABAARs in AUD, GABAARs currents and GABA pEC50 values were integrated with RNA-Seq and label-free proteomics datasets of bulk tissue and isolated synaptosomes from the same subjects. Our results outline significant reconfigurations in transcriptomic organization of GABAARs in AUD, higher levels of GABRG1 and significant decrease of mitochondrial transcripts in AUD individuals. Notably, transcriptional differences were gradually lost as the analysis moved from transcription to protein and function within our cohort. This suggests post-translational buffering in AUD resulting in unchanged GABA receptor synaptic activity. Our novel findings establish a proof of concept for reactivating AUD post-synaptic receptors and integrating this information with multiple levels of multi-omic analyses, as well as outline hypothesis-generating insights into this multifaceted disease.