Using human stem cells as a model system to understand the neural mechanisms of alcohol use disorders: Current status and outlook.

Alcohol use disorders (AUDs), which include alcohol abuse and dependence, are among the most common types of neuropsychiatric disorders in the United States (U.S.). Approximately 14% of the U.S. population is affected in a single year, thus placing a tremendous burden on individuals from all socioeconomic backgrounds. Animal models have been pivotal in revealing the basic mechanisms of how alcohol impacts neuronal function, yet there are currently limited effective therapies developed based on these studies. This is mainly due to a limited understanding of the exact cellular and molecular mechanisms underlying AUDs in humans, which leads to a lack of targeted therapeutics. Furthermore, compounding factors including genetic background, gene copy number variants, single nucleotide polymorphisms (SNP) as well as environmental and social factors that affect and promote the development of AUDs are complex and heterogeneous. Recent developments in stem cell biology, especially the human induced pluripotent stem (iPS) cell development and differentiation technologies, has provided us a unique opportunity to model neuropsychiatric disorders like AUDs in a manner that is highly complementary to animal studies, but that maintains fidelity with complex human genetic contexts. Patient-specific neuronal cells derived from iPS cells can then be used for drug discovery and precision medicine, e.g. for pathway-directed development in alcoholism. Here, we review recent work employing iPS cell technology to model and elucidate the genetic, molecular and cellular mechanisms of AUDs in a human neuronal background and provide our perspective on future development in this direction.