目的:低密度脂蛋白受体相关蛋白-1(LRP1)调节能量稳态,血脑屏障完整性,和大脑中的代谢信号。抑制性γ-氨基丁酸(GABA)能神经元中LRP1的缺乏会导致小鼠严重肥胖。然而,抑制性神经元中LRP1对肥胖患者记忆功能和认知功能的影响尚不清楚.
方法:在GABA能神经元(Vgat-Cre;LRP1loxP/loxP)中缺乏LRP1的小鼠进行了运动活动和运动协调的行为测试,短期/长期和空间记忆,和恐惧学习/记忆。这项研究评估了行为与代谢危险因素之间的关系,并追踪了16和32周龄的小鼠。
结果:在32周龄小鼠中,GABA能神经元中LRP1的缺失导致记忆功能的显著损害。在空间Y迷宫测试中,与对照(LRP1loxP/loxP小鼠)相比,Vgat-Cre;LRP1loxP/loxP小鼠在新臂中表现出减少的行进距离和持续时间。此外,GABA能神经元特异性LRP1缺陷小鼠在水T迷宫测试中表现出执行学习和记忆任务的能力减弱。此外,在上下文和提示恐惧条件测试中,在这些小鼠中观察到冷冻时间减少。这些作用伴随着海马中神经元坏死和satellitosis的增加。重要的是,小说手臂的距离和持续时间,以及反转水T迷宫测试的性能,与代谢风险参数呈负相关,包括体重,血清瘦素,胰岛素,和载脂蛋白J。然而,在16周龄的Vgat-Cre;LRP1loxP/loxP小鼠中,行为测试或代谢参数与认知之间的相关性没有差异.
结论:我们的发现表明来自GABA能神经元的LRP1在调节正常学习和记忆方面很重要。代谢,由GABA能LRP1缺失引起的肥胖以年龄依赖性方式负调节记忆和认知功能。因此,GABA能神经元中的LRP1可能在维持正常的兴奋/抑制平衡中起关键作用,影响记忆功能,并加强LRP1在神经系统完整性中的潜在重要性。
OBJECTIVE: Low-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, blood-brain barrier integrity, and metabolic signaling in the brain. Deficiency of LRP1 in inhibitory gamma-aminobutyric acid (GABA)ergic neurons causes severe obesity in mice. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in the context of obesity is poorly understood.
METHODS: Mice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1loxP/loxP) underwent behavioral tests for locomotor activity and motor coordination, short/long-term and spatial memory, and fear learning/memory. This study evaluated the relationships between behavior and metabolic risk factors and followed the mice at 16 and 32 weeks of age.
RESULTS: Deletion of LRP1 in GABAergic neurons caused a significant impairment in memory function in 32-week-old mice. In the spatial Y-maze test, Vgat-Cre; LRP1loxP/loxP mice exhibited decreased travel distance and duration in the novel arm compared with controls (LRP1loxP/loxP mice). In addition, GABAergic neuron-specific LRP1-deficient mice showed a diminished capacity for performing learning and memory tasks during the water T-maze test. Moreover, reduced freezing time was observed in these mice during the contextual and cued fear conditioning tests. These effects were accompanied by increased neuronal necrosis and satellitosis in the hippocampus. Importantly, the distance and duration in the novel arm, as well as the performance of the reversal water T-maze test, negatively correlated with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J. However, in 16-week-old Vgat-Cre; LRP1loxP/loxP mice, there were no differences in the behavioral tests or correlations between metabolic parameters and cognition.
CONCLUSIONS: Our findings demonstrate that LRP1 from GABAergic neurons is important in regulating normal learning and memory. Metabolically, obesity caused by GABAergic LRP1 deletion negatively regulates memory and cognitive function in an age-dependent manner. Thus, LRP1 in GABAergic neurons may play a crucial role in maintaining normal excitatory/inhibitory balance, impacting memory function, and reinforcing the potential importance of LRP1 in neural system integrity.