Varinthra Peeraporn, Shih Shu-Ching, Liu Ingrid Y
Institute of Medical Sciences, College of Medicine, Tzu Chi University, Hualien, Taiwan.
Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan.
Brain Behav. 2025 Jun;15(6):e70607. doi: 10.1002/brb3.70607.
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.
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 GABAα1, GABAR1, GAD67, and GABA levels in the prefrontal cortex (PFC) and hippocampus and analyze the correlations with behavioral outcomes.
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 GABAR1, decreased hippocampal GAD67, and reduced PFC GABA levels. Notably, spatial WM in 3xTg+SD and 3xTg control mice related to increased GABAα1 in the PFC and hippocampus and GAD67 in hippocampal CA1, along with decreased GABAR1 and GAD67 in the dentate gyrus.
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.
空间工作记忆（WM）衰退是阿尔茨海默病（AD）的早期特征。睡眠障碍会加剧空间工作记忆并增加患AD的风险。对睡眠调节至关重要的GABA能系统可能介导了这种联系。因此，我们研究了AD模型小鼠在快速眼动睡眠剥夺（REM-SD）期间空间工作记忆与海马GABA能信号之间的关系。
我们评估了6月龄的三转基因（3xTg）AD小鼠和野生型（WT）对照小鼠在有或没有REM-SD（5天，每天4小时）情况下的空间和非空间工作记忆、运动活动以及焦虑样行为。然后，我们使用免疫荧光法对前额叶皮质（PFC）和海马中的GABAα1、GABAR1、GAD67和GABA水平进行定量，并分析其与行为结果的相关性。
REM-SD增加了3xTg-AD小鼠的运动活动，减少了焦虑样行为，并改善了非空间工作记忆。相反，REM-SD损害了WT小鼠的空间工作记忆，这在3xTg-AD小鼠中也得到了证实。海马GABA水平升高与3xTg+SD小鼠非空间工作记忆的改善相关。相比之下，WT+SD小鼠空间工作记忆受损与海马GABA和GABAR1升高、海马GAD67降低以及PFC GABA水平降低有关。值得注意的是，3xTg+SD和3xTg对照小鼠的空间工作记忆与PFC和海马中GABAα1增加以及海马CA1中GAD67增加有关，同时齿状回中GABAR1和GAD67减少。
REM-SD引起的工作记忆表现改变与PFC和海马中的GABA能信号变化有关，WT和3xTg-AD小鼠呈现出不同的模式。本研究为AD病理学以及睡眠相关认知障碍的潜在治疗靶点提供了见解。
