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.

Keywords: Alzheimer's disease; GABA; rapid eye movement; sleep deprivation; working memory.

© 2025 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.

简介： 空间工作记忆（WM）的下降是阿尔茨海默病（AD）早期的一个标志性特征。睡眠障碍会加剧空间工作记忆衰退并增加患AD的风险。作为睡眠调节的关键系统，GABA能系统的功能可能介导这一关联。因此，我们研究了在AD模型小鼠中快速眼动睡眠剥夺（REM-SD）期间空间WM与海马体GABA能信号之间的关系。

方法： 我们评估了6月龄三转基因（3xTg）AD小鼠和野生型（WT）对照组在有无REM-SD（5天，每天4小时）条件下的空间和非空间WM、运动活动以及焦虑样行为。然后我们使用免疫荧光技术量化前额皮质（PFC）和海马体中的GABA_Aα1、GABA_BR1、GAD67及GABA水平，并分析其与行为结果之间的相关性。

结果： REM-SD使3xTg-AD小鼠的运动活动增加，焦虑样行为减少，并且改善了非空间WM。相反，REM-SD在WT小鼠中损害了空间WM，在3xTg-AD小鼠中也观察到了类似的效果。在3xTg+SD小鼠中，海马体GABA水平升高与非空间WM的改进相关联。相比之下，在WT+SD小鼠中，损害的空间WM与升高的海马体GABA和GABA_BR1、降低的海马体GAD67以及PFC GABA水平下降有关。值得注意的是，3xTg+SD和3xTg对照组小鼠的空间WM与PFC和海马体中的增加GABA_Aα1及海马CA1区GAD67的升高相关联，并且海马齿状回中GABA_BR1和GAD67水平降低。

结论： REM-SD引起的WM表现变化与PFC和海马体中的GABA能信号改变有关，WT小鼠和3xTg-AD小鼠表现出不同的模式。本研究为理解AD病理学以及潜在的睡眠相关认知障碍治疗靶点提供了见解。

关键词： 阿尔茨海默病；GABA；快速眼动；睡眠剥夺；工作记忆。