Microglia-like cells derived from patients with obsessive-compulsive disorder and social anxiety disorder
Microglia are central to neuroimmune surveillance and synaptic remodeling, yet their contribution to obsessive–compulsive disorder (OCD) remains unclear. Here, we generated patient-derived microglia-like cells (iMGs) from OCD (n = 19), social anxiety disorder (SAD; n = 16), and healthy control (HC; n = 20) participants to identify the molecular and functional alterations in OCD-iMGs and to find therapeutic targets capable of restoring their functions. Bulk transcriptomic profiling of iMGs identified a selective reduction of MDM2 in OCD-iMGs. Notably, MDM2 mRNA was negatively correlated with Dimensional Obsessive-Compulsive Scale (DOCS) scores. Functional assays in siRNA-transfected primary microglia demonstrated that MDM2 knockdown impaired synaptosome phagocytosis and blunted LPS induced inflammatory responses, validating MDM2 as a mechanistic node. A Connectivity Map analysis nominated bortezomib, and subsequent experiments showed that bortezomib restored MDM2 expression and rescued phagocytic and immune functions in both MDM2-deficient microglia and OCD-iMGs. Collectively, these findings implicate microglial MDM2 reduction as a feature of OCD with direct functional consequences. Overall design: Human RNA samples isolated from peripheral blood monocyte–derived microglia-like cells of 13 healthy controls, 13 obsessive-compulsive disorder patients, and 11 social anxiety disorder patients were sequenced.