Disease modeling in human pluripotent stem cell-derived prefrontal cortex neurons

Major depressive disorder (MDD) is a complex multifactorial neuropsychiatric disorder involving both genetic and environmental factors. While several risk factors for depression have been established, their effect on human neuronal function and potential shared disease-associated cellular or molecular phenotypes across different risk factors remain elusive. Here, we have developed a combined genetic/pharmacological disease modeling strategy in human pluripotent stem cell (hPSC)-derived prefrontal cortex (PFC) neurons, a cell type whose dysfunction is consistently associated with depression, to capture depression-associated cellular phenotypes and molecular correlates across three depression models. Our study identified largely convergent MDD-associated neuronal phenotypes characterized by neuronal atrophy and hypoactivity and identified alterations in neuronal cholesterol homeostasis as a driver of these phenotypes. This work highlights the potential of hPSC-derived models to uncover cellular and molecular phenotypes associated with neuropsychiatric disorders such as depression and illustrates how they can be used to reveal convergent, disease-associated features across different pharmacological and genetic models.