The NLRP3 inflammasome in microglia regulates repetitive behavior by modulating NMDA glutamate receptor functions
Hyeji Jung,
Byeongchan Kim,
Gyubin Jang,
Hyeonho Kim,
Ae-Ree Lee,
Sung-Hyun Yoon,
Kyung-Seo Lee,
Gaeun Hyun,
Younghye Kim,
Jaewon Ko,
Je-Wook Yu,
Ji Won Um
Affiliations
Hyeji Jung
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea; Center for Synapse Diversity and Specificity, DGIST, 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea
Byeongchan Kim
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea
Gyubin Jang
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea; Center for Synapse Diversity and Specificity, DGIST, 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea
Hyeonho Kim
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea; Center for Synapse Diversity and Specificity, DGIST, 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea
Ae-Ree Lee
Core Protein Resources Center, DGIST, Daegu 42988, Korea; iProteinTherapeutics (iPT), Daegu 42988, Korea
Sung-Hyun Yoon
Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
Kyung-Seo Lee
Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
Gaeun Hyun
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea
Younghye Kim
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea; Center for Synapse Diversity and Specificity, DGIST, 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea
Jaewon Ko
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea; Center for Synapse Diversity and Specificity, DGIST, 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea
Je-Wook Yu
Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
Ji Won Um
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea; Center for Synapse Diversity and Specificity, DGIST, 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea; Corresponding author
Summary: 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 Nlrp3D301N-cKI mice. Collectively, our results demonstrate that NLRP3-mediated neuroinflammation elicits repetitive behavior through impaired NMDAR functions.
