Abstract <p>Focal cortical dysplasia (FCD) is one of the major causes of refractory epilepsy. Evidence suggests that neuroinflammation contributes to the epileptogenesis of FCD. Downregulation of cluster of differentiation 200 (CD200) leads to neuroinflammation. We previously reported decreased expression of CD200 in brain lesions of FCD patients. In this study, we examined the expression and influences of CD200 on epileptogenesis in a mouse model of FCD. Video monitoring revealed an increased number of motor seizures in cd200 knockout (cd200^–/–) FCD mice compared to the wild-type (WT) FCD mice, and CD200 fusion protein (CD200 Fc) downregulated the number of motor seizures in WT FCD mice. Western blotting results displayed a decreased protein expression of CD200 in FCD mice versus the control groups (CTX), and the relative protein level of CD200 is negatively correlated with motor seizure occurrence. Immunohistochemistry and double-labeled immunofluorescence showed that CD200 was expressed in neurons and astrocytes, not in microglia. Correlation analysis revealed a negative correlation between the immunoreactivity (IR) scores of CD200 and the number of ionized calcium binding adaptor molecule 1 (IBA1)-positive microglia. Enzyme-linked immune sorbent assays (ELISAs) showed that the production of interleukin-1β (IL-1β), IL-6, and IL-17 was upregulated in cd200^–/– FCD compared to the CTX. In addition, CD200 Fc could downregulate the expression of IL-1β, IL-6, and IL-17, and up-regulate the expression of downstream of tyrosine kinase 2 (Dok2), which is the downstream molecular of the CD200 pathway. Our findings suggest that&#xa0;CD200 may play a pivotal role in the epileptogenesis of FCD.</p>