In this study, Jung et al. investigate the effect of excessive NLRP3-mediated neuroinflammation on synaptic functions and behaviors using Nlrp3D301N-conditional knockin mice. Strikingly, excessive NLRP3-mediated neuroinflammation causes NMDAR hyperactivation, leading to abnormal behaviors. Treatment with IL-1β receptor antagonist (IL-1RA) or NMDAR antagonist reverses the pathological phenotypes.