Additional recent technical advances that provide insights into the impact of brain-derived alcohol metabolism are the generation of pre-clinical models that allow the investigation of cell-type-specific ALDH2 distributions in a brain-region-specific manner (139). These studies suggest that acetate produced by astrocytic ALDH2 in the cerebellum plays a key role in ethanol-induced GABA synthesis and motor impairment (139). By generating mice with astrocytic or hepatocytic ALDH2 deficiency, Jin and collaborators showed that acetate derived from central—rather than peripheral—ethanol metabolism primarily drove the synthesis of gamma-aminobutyric acid (GABA), the most common inhibitory neurotransmitter in the brain after low-dose ethanol administration. Notably, they also found that the cerebellum exhibited the highest levels of ALDH2 mRNA expression in both mice and humans, suggesting potential translational relevance (139).
