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However, the molecular mechanism by which convulsive SE leads to neuronal damage is not completely understood. Cathepsin S (Ctss), a lysosomal cysteine protease, has been implicated in secondary injury after traumatic brain injury. This study sought to explore whether Ctss is also involved in SE\u2010induced neuronal damage in the hippocampus. Immunohistochemistry and Western blotting were utilized to detect the expression of Ctss in the hippocampal subregions of male C57BL\/6J mice at various times following kainic acid (KA)\u2013induced SE. The reactivity of microglia was assessed using immunohistochemistry, and Fluoro\u2010Jade C (FJC) staining was employed to identify damaged neurons. We found that the mature form of Ctss is barely observed in na\u00efve adult (12\u2010week\u2010old) mouse hippocampus, but its expression is significantly evident at 50\u2009weeks of age. In adult mice, the expression of both pro\u2010and mature forms of Ctss in the hippocampal CA3 region was increased as early as 16\u2009h following KA\u2010induced SE. The increased Ctss immunoreactivity was mainly found in microglia following KA\u2010induced SE. The damaged neurons visualized by FJC staining were prominent in the CA3 region at 16\u2009h following KA\u2010induced SE.\n                    <jats:italic>Ctss<\/jats:italic>\n                    knockdown did not affect KA\u2010induced behavioral seizures but significantly reduced SE\u2010induced microglia activation and neuronal damage. An increase in chemokine CX3C motif ligand 1 (CX3CL1) immunoreactivity on microglia was observed following KA\u2010induced SE, and CX3C motif chemokine receptor 1 (CX3CR1) antagonist AZD8797 treatment significantly attenuated SE\u2010induced microglia activation and neuronal damage. Altogether, these results indicate a crucial role of Ctss in SE\u2010induced neuronal damage, possibly through CXC3L1\u2010mediated microglial activation, and provide a new perspective for preventing SE\u2010induced neuronal damage.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70037-fig-0009-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70037","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T01:30:45Z","timestamp":1741743045000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Upregulation of 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