GABAergic Signaling Underlying REM Sleep Deprivation‐Induced Spatial Working Memory Deficits
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2025
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| author | Peeraporn Varinthra Shu‐Ching Shih Ingrid Y Liu |
| author_facet | Peeraporn Varinthra Shu‐Ching Shih Ingrid Y Liu Peeraporn Varinthra Shu‐Ching Shih Ingrid Y Liu |
| collection | Wiley Open Access |
| contents | GABAergic Signaling Underlying REM Sleep Deprivation‐Induced Spatial Working Memory Deficits Peeraporn Varinthra Shu‐Ching Shih Ingrid Y Liu Brain and Behavior ABSTRACTIntroductionDeclining 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.MethodsWe 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.ResultsREM‐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.ConclusionREM‐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. 10.1002/brb3.70607 http://creativecommons.org/licenses/by/4.0/ |
| doi_str_mv | 10.1002/brb3.70607 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_brb3_70607 |
| institution | Wiley Open Access |
| license_str_mv | http://creativecommons.org/licenses/by/4.0/ |
| publishDate | 2025 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | GABAergic Signaling Underlying REM Sleep Deprivation‐Induced Spatial Working Memory Deficits Peeraporn Varinthra Shu‐Ching Shih Ingrid Y Liu Brain and Behavior GABAergic Signaling Underlying REM Sleep Deprivation‐Induced Spatial Working Memory Deficits Peeraporn Varinthra Shu‐Ching Shih Ingrid Y Liu Brain and Behavior ABSTRACTIntroductionDeclining 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.MethodsWe 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.ResultsREM‐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.ConclusionREM‐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. 10.1002/brb3.70607 http://creativecommons.org/licenses/by/4.0/ |
| title | GABAergic Signaling Underlying REM Sleep Deprivation‐Induced Spatial Working Memory Deficits |
| topic | Brain and Behavior |
| url | https://onlinelibrary.wiley.com/doi/10.1002/brb3.70607 |