GABAergic Signaling Underlying REM Sleep Deprivation-Induced Spatial Working Memory Deficits

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 GABA_Aα1, GABA_BR1, 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 GABA_BR1, decreased hippocampal GAD67, and reduced PFC GABA levels. Notably, spatial WM in 3xTg+SD and 3xTg control mice related to increased GABA_Aα1 in the PFC and hippocampus and GAD67 in hippocampal CA1, along with decreased GABA_BR1 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.