GABAergic Signaling Underlying REM Sleep Deprivation‐Induced Spatial Working Memory Deficits
ABSTRACT Introduction Declining spatial working memory (WM) is an early hallmark of Alzheimer's disease (AD). 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 s...
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Wiley
2025-06-01
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| Series: | Brain and Behavior |
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| Online Access: | https://doi.org/10.1002/brb3.70607 |
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| author | Peeraporn Varinthra Shu‐Ching Shih Ingrid Y Liu |
| author_facet | Peeraporn Varinthra Shu‐Ching Shih Ingrid Y Liu |
| author_sort | Peeraporn Varinthra |
| collection | DOAJ |
| description | ABSTRACT Introduction Declining spatial working memory (WM) is an early hallmark of Alzheimer's disease (AD). 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‐SD) in AD model mice. Methods We assessed spatial and non‐spatial WM, locomotor activity, and anxiety‐like behavior in 6‐month‐old triple transgenic (3xTg) AD mice and wild‐type (WT) controls, with and without REM‐SD (5 days, 4 h/day). We then used immunofluorescence to quantify GABAAα1, GABABR1, GAD67, and GABA levels in the prefrontal cortex (PFC) and hippocampus and analyze the correlations with behavioral outcomes. Results REM‐SD increased locomotor activity, reduced anxiety‐like behavior, and improved non‐spatial WM in 3xTg‐AD mice. Conversely, REM‐SD impaired spatial WM in WT mice, which was also demonstrated in 3xTg‐AD mice. Increased hippocampal GABA levels are correlated with improved non‐spatial WM in 3xTg+SD mice. In contrast, impaired spatial WM in WT+SD mice was associated with elevated hippocampal GABA and GABABR1, decreased hippocampal GAD67, and reduced PFC GABA levels. Notably, spatial WM in 3xTg+SD and 3xTg control mice related to increased GABAAα1 in the PFC and hippocampus and GAD67 in hippocampal CA1, along with decreased GABABR1 and GAD67 in the dentate gyrus. Conclusion REM‐SD‐induced alterations in WM performance are linked to GABAergic signaling changes in the PFC and hippocampus, with distinct patterns in WT and 3xTg‐AD mice. This study provides insight into AD pathologies and potential therapeutic targets for sleep‐related cognitive impairments. |
| format | Article |
| id | doaj-art-eef7037b10464b8095d9507a4afc9a6e |
| institution | DOAJ |
| issn | 2162-3279 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Brain and Behavior |
| spelling | doaj-art-eef7037b10464b8095d9507a4afc9a6e2025-08-20T03:02:45ZengWileyBrain and Behavior2162-32792025-06-01156n/an/a10.1002/brb3.70607GABAergic Signaling Underlying REM Sleep Deprivation‐Induced Spatial Working Memory DeficitsPeeraporn Varinthra0Shu‐Ching Shih1Ingrid Y Liu2Institute of Medical Sciences, College of Medicine Tzu Chi University Hualien TaiwanDepartment of Molecular Biology and Human Genetics Tzu Chi University Hualien TaiwanInstitute of Medical Sciences, College of Medicine Tzu Chi University Hualien TaiwanABSTRACT Introduction Declining spatial working memory (WM) is an early hallmark of Alzheimer's disease (AD). 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‐SD) in AD model mice. Methods We assessed spatial and non‐spatial WM, locomotor activity, and anxiety‐like behavior in 6‐month‐old triple transgenic (3xTg) AD mice and wild‐type (WT) controls, with and without REM‐SD (5 days, 4 h/day). We then used immunofluorescence to quantify GABAAα1, GABABR1, GAD67, and GABA levels in the prefrontal cortex (PFC) and hippocampus and analyze the correlations with behavioral outcomes. Results REM‐SD increased locomotor activity, reduced anxiety‐like behavior, and improved non‐spatial WM in 3xTg‐AD mice. Conversely, REM‐SD impaired spatial WM in WT mice, which was also demonstrated in 3xTg‐AD mice. Increased hippocampal GABA levels are correlated with improved non‐spatial WM in 3xTg+SD mice. In contrast, impaired spatial WM in WT+SD mice was associated with elevated hippocampal GABA and GABABR1, decreased hippocampal GAD67, and reduced PFC GABA levels. Notably, spatial WM in 3xTg+SD and 3xTg control mice related to increased GABAAα1 in the PFC and hippocampus and GAD67 in hippocampal CA1, along with decreased GABABR1 and GAD67 in the dentate gyrus. Conclusion REM‐SD‐induced alterations in WM performance are linked to GABAergic signaling changes in the PFC and hippocampus, with distinct patterns in WT and 3xTg‐AD mice. This study provides insight into AD pathologies and potential therapeutic targets for sleep‐related cognitive impairments.https://doi.org/10.1002/brb3.70607Alzheimer's diseaseGABArapid eye movementsleep deprivationworking memory |
| spellingShingle | Peeraporn Varinthra Shu‐Ching Shih Ingrid Y Liu GABAergic Signaling Underlying REM Sleep Deprivation‐Induced Spatial Working Memory Deficits Brain and Behavior Alzheimer's disease GABA rapid eye movement sleep deprivation working memory |
| title | GABAergic Signaling Underlying REM Sleep Deprivation‐Induced Spatial Working Memory Deficits |
| title_full | GABAergic Signaling Underlying REM Sleep Deprivation‐Induced Spatial Working Memory Deficits |
| title_fullStr | GABAergic Signaling Underlying REM Sleep Deprivation‐Induced Spatial Working Memory Deficits |
| title_full_unstemmed | GABAergic Signaling Underlying REM Sleep Deprivation‐Induced Spatial Working Memory Deficits |
| title_short | GABAergic Signaling Underlying REM Sleep Deprivation‐Induced Spatial Working Memory Deficits |
| title_sort | gabaergic signaling underlying rem sleep deprivation induced spatial working memory deficits |
| topic | Alzheimer's disease GABA rapid eye movement sleep deprivation working memory |
| url | https://doi.org/10.1002/brb3.70607 |
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