{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:35:34Z","timestamp":1791246934992,"version":"4.1.0"},"reference-count":71,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T00:00:00Z","timestamp":1741910400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>The locus coeruleus (LC) is one of the earliest brain regions affected by phosphorylated tau (p\u2010tau) in Alzheimer's disease (AD). Using the P301S mouse model, we investigated the temporal progression of tau pathology and its functional consequences.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Immunohistochemistry was used to assess p\u2010tau deposition in LC noradrenergic neurons at 2\u20133 and 5\u20136\u2009months. Electrophysiological recordings evaluated neuronal hyperexcitability, measuring membrane potential, rheobase, and spontaneous action potential (AP) frequency in P301S and wild\u2010type (WT) mice. Fast\u2010scan cyclic voltammetry (FSCV) was used to measure norepinephrine (NE) release. GABA(A) receptor subunit expression was analyzed via immunoblotting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>P\u2010tau was detected in LC neurons as early as 2\u20133\u2009months, with a rostral\u2010to\u2010caudal gradient, and by 5\u20136\u2009months, nearly all LC neurons exhibited p\u2010tau immunoreactivity. P301S neurons showed hyperexcitability, characterized by depolarized membrane potentials, a more negative rheobase, and increased spontaneous AP frequency. Synaptic blockade elicited a reduced increase in AP frequency, suggesting diminished inhibitory tone. GABA(A) \u03b12 subunit expression significantly declined with age in P301S mice, whereas \u03b13 remained unchanged. FSCV showed significantly elevated NE release in P301S mice at 3 and 6\u2009months compared to WT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The findings highlight early LC dysfunction in tauopathies, characterized by increased excitability, reduced inhibitory tone, and exaggerated NE release. This hyperactivity may contribute to excitotoxicity and downstream dysfunction in LC\u2010regulated brain regions. Targeting LC hyperactivity and restoring inhibitory signaling could be promising therapeutic strategies for mitigating AD progression.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.70022","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T07:39:19Z","timestamp":1741937959000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Early signs of neuron autonomous and non\u2010autonomous hyperexcitability in locus coeruleus noradrenergic neurons of a mouse model of tauopathy and Alzheimer's disease"],"prefix":"10.1111","volume":"241","author":[{"given":"Zhong\u2010Min","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Gerontology and Geriatric Medicine Wake Forest University School of Medicine  Winston\u2010Salem North Carolina 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