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

Alterations of GABA_A receptors (GABA_ARs) 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_ARs 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_ARs. To follow the path from transcription to function of potential changes of GABA_ARs in AUD, GABA_ARs 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 GABA_ARs 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.