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Pathological, aggregated forms of tau form neurofibrillary tangles (NFTs), impairing its ability to stabilize microtubules and promoting neurotoxicity. Indeed, NFTs correlate with neuronal loss and cognitive impairment. Hyperphosphorylation of tau is seen in all tauopathies and mirrors disease progression, suggesting an essential role in pathogenesis. However, hyperphosphorylation remains a generic and ill\u2010defined term, obscuring the functional importance of specific sites in different physiological or pathological settings. Here, we focused on global mapping of tau phosphorylation specifically during conditions of neuronal hyperexcitation. Hyperexcitation is a property of AD and other tauopathies linked to human cognitive deficits and increased risk of developing seizures and epilepsy. Moreover, hyperexcitation promotes extracellular secretion and trans\u2010synaptic propagation of tau. Using unbiased mass spectrometry, we identified a novel phosphorylation signature in the C\u2010terminal domain of tau detectable only during neuronal hyperactivity in primary cultured rat hippocampal neurons. These sites influenced tau localization to dendrites as well as the size of excitatory postsynaptic sites. These results demonstrate novel physiological tau functions at synapses and the utility of comprehensive analysis of tau phosphorylation during specific signaling contexts.\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\/jnc16221-fig-0006-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16221","type":"journal-article","created":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T12:32:16Z","timestamp":1734611536000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mass spectrometry identifies tau C\u2010terminal phosphorylation cluster during neuronal hyperexcitation"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4141-6064","authenticated-orcid":false,"given":"Amanda","family":"Schneeweis","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Physiology Georgetown University Medical Center  Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawson","family":"Hillyer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology Georgetown University Medical Center  Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsering","family":"Lama","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology Georgetown University Medical Center  Washington District of Columbia 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