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Here, we demonstrated that in the absence of changes in inflammatory factors IL-18, IL-1\u03b2 and TNF-\u03b1, neuronal Nlrp3 knockout in hippocampus (nNlrp3\n                    <jats:sup>-\/-<\/jats:sup>\n                    ) improved long-term spatial memory performance, with increased synaptic proteins levels and enhanced amplitude of long-term potentiation at 4 weeks after traumatic brain injury (TBI), compared to wildtype littermates. Notably, the nNlrp3\n                    <jats:sup>-\/-<\/jats:sup>\n                    mice out-performed microglia-specific knockout and global Nlrp3 knockout mice in cognition and synaptic function. We further identified that NLRP3 structurally and functionally directly interacted with the R1 subunit of N-methyl-D-aspartate receptor (NR1) in hippocampus after TBI. Accordingly, pharmacological inhibition of NLRP3 by MCC950 rescued the decrease in the NMDAR-gated calcium influx by LPS-stimulated hippocampal neurons while selective Nlrp3 knockout in hippocampal neurons partially reversed the decreased phosphorylation level of NR1 after TBI. Collectively, this study provides the first evidence that neuronal NLRP3 constitutes a non-inflammatory response to control synaptic plasticity and cognitive function via NR1-dependent non-inflammatory mechanism in TBI and thus broadens the central role of NLRP3 in neuronal adaptive mechanisms to include both microglial NLRP3-inflammation arm and the neuronal NLRP3-synaptic plasticity arm.\n                  <\/jats:p>","DOI":"10.1038\/s41380-026-03954-0","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T10:02:32Z","timestamp":1792749752000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The non-inflammatory effect of neuronal NLRP3 on spatial memory after traumatic brain injury"],"prefix":"10.1038","author":[{"given":"Si-Wei","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4926-3835","authenticated-orcid":false,"given":"Ping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Lei","family":"Ning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruo-Bing","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Hong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Guo","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9203-4749","authenticated-orcid":false,"given":"Yan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,23]]},"reference":[{"key":"3954_CR1","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/s41582-023-00915-x","volume":"20","author":"KA Ravichandran","year":"2024","unstructured":"Ravichandran KA, Heneka MT. 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