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Synaptotagmin\u20103 (Syt3), a synaptic calcium sensor, exacerbates ischemic injury by promoting pathological glutamate release. This study investigated the potential neuroprotective effect of restriction of Syt3 internalization on neuronal apoptosis and microglial reprogramming following ischemia\/reperfusion (I\/R).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The effects of Tat\u2010GluA2\u20103Y (3Y), a cell\u2010permeable peptide inhibitor of Syt3 internalization, were studied in a mouse model of middle cerebral artery occlusion\/reperfusion (MCAO\/R) and in oxygen\u2013glucose deprivation\/reperfusion (OGD\/R)\u2010induced HT22 and BV2 cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The peptide 3Y treatment significantly reduced infarct volume, brain edema, and improved neurological deficits. Additionally, it reduced neuronal apoptosis and also inhibited neuroinflammation by down\u2010regulating the level of IL\u20101b, TNF\u2010a, and iNOS but up\u2010regulating the level of TGF\u2010b1 and Arg\u20101. Single\u2010nucleus RNA sequencing of the peri\u2010infarct region revealed a dual mechanism: 3Y suppressed pro\u2010apoptotic gene programs in neurons and facilitated the transformation between different phenotypes of microglia via the cAMP pathway from a pro\u2010inflammatory to an anti\u2010inflammatory and immune\u2010protective state. In\u00a0vitro, 3Y attenuated oxygen\u2013glucose deprivation\u2010induced neuronal death and instructed microglia to adopt a protective, TGF\u2010\u03b21\u2010secreting phenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, our findings establish the inhibition of Syt3 internalization as a novel therapeutic strategy that concurrently protects neurons and reprograms the microglial immune response, offering a promising dual\u2010mechanism approach for acute stroke therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.70815","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T09:46:15Z","timestamp":1772963175000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Restricting Synaptotagmin\u20103 Internalization Mitigates Cerebral Ischemia\/Reperfusion Injury by Curtailed Neuronal Apoptosis and Microglial Re\u2010Programming"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9253-4357","authenticated-orcid":false,"given":"Hua","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Neurology First Affiliated Hospital of Soochow University  Suzhou China"},{"name":"Department of Neurology Jintan Affiliated Hospital of Jiangsu University, Changzhou Jintan First People's Hospital  Changzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongbo","family":"Mi","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neuropsychiatric Diseases &amp; College of Pharmaceutical Sciences, Soochow University  Suzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong","family":"Cheng","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neuropsychiatric Diseases &amp; College of 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