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Sleep disturbance exacerbates spatial WM and increases AD risk. The GABAergic system, crucial for sleep regulation, may mediate this link. We thus investigate the relationship between spatial WM and hippocampal GABAergic signaling during rapid eye movement sleep deprivation (REM\u2010SD) in AD model mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed spatial and non\u2010spatial WM, locomotor activity, and anxiety\u2010like behavior in 6\u2010month\u2010old triple transgenic (3xTg) AD mice and wild\u2010type (WT) controls, with and without REM\u2010SD (5 days, 4 h\/day). We then used immunofluorescence to quantify GABA<jats:sub>A<\/jats:sub>\u03b11, GABA<jats:sub>B<\/jats:sub>R1, GAD67, and GABA levels in the prefrontal cortex (PFC) and hippocampus and analyze the correlations with behavioral outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>REM\u2010SD increased locomotor activity, reduced anxiety\u2010like behavior, and improved non\u2010spatial WM in 3xTg\u2010AD mice. Conversely, REM\u2010SD impaired spatial WM in WT mice, which was also demonstrated in 3xTg\u2010AD mice. Increased hippocampal GABA levels are correlated with improved non\u2010spatial WM in 3xTg+SD mice. In contrast, impaired spatial WM in WT+SD mice was associated with elevated hippocampal GABA and GABA<jats:sub>B<\/jats:sub>R1, decreased hippocampal GAD67, and reduced PFC GABA levels. Notably, spatial WM in 3xTg+SD and 3xTg control mice related to increased GABA<jats:sub>A<\/jats:sub>\u03b11 in the PFC and hippocampus and GAD67 in hippocampal CA1, along with decreased GABA<jats:sub>B<\/jats:sub>R1 and GAD67 in the dentate gyrus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>REM\u2010SD\u2010induced alterations in WM performance are linked to GABAergic signaling changes in the PFC and hippocampus, with distinct patterns in WT and 3xTg\u2010AD mice. This study provides insight into AD pathologies and potential therapeutic targets for sleep\u2010related cognitive impairments.<\/jats:p><\/jats:sec>","DOI":"10.1002\/brb3.70607","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T03:30:21Z","timestamp":1748835021000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["GABAergic Signaling Underlying REM Sleep Deprivation\u2010Induced Spatial Working Memory Deficits"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8070-5016","authenticated-orcid":false,"given":"Peeraporn","family":"Varinthra","sequence":"first","affiliation":[{"name":"Institute of Medical Sciences, College of Medicine Tzu Chi University  Hualien Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu\u2010Ching","family":"Shih","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and 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