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Recently, a hypothesis has emerged suggesting that tau propagation is linked to functional neuronal connections, specifically driven by neuronal hyperactivity. However, experimental validation of this hypothesis remains limited. In this study, we investigated how tau propagation from the entorhinal cortex to the hippocampus, the neuronal circuit most susceptible to tau pathology in AD, is affected by the selective stimulation of neuronal activity along this circuit. Using a mouse model of seed-induced propagation combined with optogenetics, we found that the chronic stimulation of this neuronal connection over a 4-week period resulted in a significant increase in insoluble tau accumulation in both the entorhinal cortex and hippocampus. Importantly, the ratio of tau accumulation in the hippocampus relative to that in the entorhinal cortex, serving as an indicator of transcellular spreading, was significantly higher in mice subjected to chronic stimulation. These results support the notion that abnormal neuronal activity promotes tau propagation, thereby implicating it in the progression of tauopathy.<\/jats:p>","DOI":"10.3390\/ijms25169004","type":"journal-article","created":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T10:11:28Z","timestamp":1724062288000},"page":"9004","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Chronic Neuronal Hyperexcitation Exacerbates Tau Propagation in a Mouse Model of Tauopathy"],"prefix":"10.3390","volume":"25","author":[{"given":"Itaru","family":"Nishida","sequence":"first","affiliation":[{"name":"Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 1130033, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3696-0604","authenticated-orcid":false,"given":"Kaoru","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 1130033, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asami","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 1130033, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7109-7741","authenticated-orcid":false,"given":"Tomoko","family":"Wakabayashi","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 1130033, Japan"},{"name":"Department of Pathophysiology, Meiji Pharmaceutical University, Tokyo 2040004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Iwatsubo","sequence":"additional","affiliation":[{"name":"National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 1878551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/0197-4580(95)00021-6","article-title":"Staging of Alzheimer\u2019s Disease-Related Neurofibrillary Changes","volume":"16","author":"Braak","year":"1995","journal-title":"Neurobiol. 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