MDM2-linked microglial dysfunction in obsessive-compulsive disorder

Microglia, the resident immune cells of the central nervous system, are essential for immune surveillance and synaptic remodeling, and have been implicated in various neuropsychiatric disorders. However, their role in the pathophysiology of obsessive-compulsive disorder (OCD) remains unclear. Here we identify molecular and functional impairments in induced microglia-like cells (iMGs) derived from peripheral monocytes of OCD patients (n=23), compared with those from healthy controls (HC, n=24) and individuals with social anxiety disorder (SAD, n=16). Transcriptomic profiling revealed a selective reduction of Murine double minute 2 (MDM2) expression in OCD-iMGs, which correlated inversely with symptom severity measured by the dimensional obsessive-compulsive scale (DOCS) total score. Functional knockdown (KD) of MDM2 in primary microglia impaired synaptosome phagocytosis and dampened inflammatory responses to lipopolysaccharide (LPS). In addition, MDM2 KD microglia showed reduction of furin and mature BDNF (brain-derived neurotrophic factor) expression. Drug screening using Connectivity Map identified bortezomib (BTZ) as a candidate compound capable of reversing the OCD-associated microglial features. BTZ restored MDM2 expression and mBDNF, leading to restoration of phagocytic function in MDM2 KD microglia and OCD-iMGs. Finally, BTZ attenuatedrepetitive behaviors in a serotonergic mouse model, suggesting that the MDM2–BDNF pathway may represent a candidate target in OCD.