The NLRP3 inflammasome in microglia regulates repetitive behavior by modulating NMDA glutamate receptor functions.

Neuroinflammation is a well-established risk factor for various neurological disorders and cognitive decline. However, the precise molecular mechanisms linking inflammation with neuropsychiatric symptoms remain unclear. Here, using NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) conditional knockin (cKI) mice harboring a D301N point mutation originating in patients with autoinflammatory diseases, we found that activation of the NLRP3 inflammasome by administration of lipopolysaccharide induced anxiety-like and repetitive behaviors frequently found in patients with neuropsychiatric disorders, as well as increasing NMDAR (N-methyl-D-aspartate receptor)-mediated excitatory synaptic functions in the medial prefrontal cortex of mice. In addition, interleukin 1β (IL-1β), a downstream cytokine of the NLRP3 inflammasome, enhanced NMDAR activation and increased surface levels of the selective NMDAR subunit GluN2A in cultured cortical neurons. Strikingly, treatment with an NMDAR antagonist or IL-1 receptor antagonist completely normalized the specific behavioral deficits in Nlrp3^D301N-cKI mice. Collectively, our results demonstrate that NLRP3-mediated neuroinflammation elicits repetitive behavior through impaired NMDAR functions.