Environmental and genetic risk factors of depression converge on neuronal dysfunction driven by changes in cholesterol homeostasis.

Major depressive disorder (MDD) is a complex, multifactorial neuropsychiatric disorder influenced by both genetic and environmental factors, but how these factors impact human neuronal function remains unclear. Using a highly defined human pluripotent stem cell (hPSC)-based prefrontal cortex (PFC) platform, we examined three high-confidence environmental and genetic factors associated with depression: chronic exposure to high levels of cortisol or interferon alpha (IFN-a), and a mutation in SIRTUIN 1 (SIRT1). All three conditions induced overlapping phenotypes of neuronal dysfunction, characterized by dendritic atrophy, synaptic loss, and neuronal hypoactivity across multiple cell lines. RNA sequencing uncovered converging alterations in neuronal cholesterol homeostasis. Depleting cholesterol in control neurons reproduced core depression-associated neuronal phenotypes, while cholesterol supplementation was sufficient to rescue these phenotypes in depression-associated conditions. These findings point to cholesterol imbalance as a common driver of neuronal dysfunction in MDD, linking diverse genetic and environmental risk factors through a shared cellular pathway.