Altered neuroinflammatory signaling in microglia has previously been reported in postmortem brains from individuals with OUD5,9. Several DEGs in microglia lend further support roles for inflammation in synaptic plasticity in OUD. For example, the PAX-FOXO1, CDH1, and neuron projection signaling pathways were enriched among microglia DEGs (FDR < 0.049). PAX-FOXO1 signaling regulates cellular senescence in the brain and is involved in the pathogenesis of several neurodegenerative disorders85, while CDH1 signaling is involved in glial cell migration and axonal projections86. In the neuronal projection pathway, ADGRB3 was among the top downregulated genes in microglia of individuals with OUD (FDR = 3.5e-7). ADGRB3 (known as BAI3, brain-specific angiogenesis inhibitor 3) encodes for a protein that has high-affinity for complement, C1q, an innate immune component released by neurons to eliminate damaged or inactive synapses87. Downregulation of ADGRB3 in microglia may lead to aberrant synaptic formation.
