Zhang Zihan, Guo Shuhan, Li Mingyue, Shao Kuiyang, Xiao Bin, Jin Qinghua
Department of Physiology and Pathophysiology, Medical College, Yanbian University, Yanji 133002, China.
Key Laboratory of Cellular Function and Pharmacology of Jilin Province, Yanbian University, Yanji, China.
Behav Brain Res. 2025 Sep 13;493:115685. doi: 10.1016/j.bbr.2025.115685. Epub 2025 Jun 2.
The hippocampal dentate gyrus (DG) integrates multiple sensory inputs and encodes spatial memory. DG-dependent spatial memory deficits have been observed in early Alzheimer's disease (AD). Our previous study demonstrated that glutamate (Glu)-mediated excitotoxicity contributes to spatial learning and memory impairment in AD. It has been reported that the N-methyl-D-aspartic acid receptor (NMDAR) 2B subunit (NR2B) is predominantly localized to extrasynaptic sites, where it is associated with Ca²⁺ neurotoxicity and neuronal loss. However, the specific contribution of NR2B-mediated excitotoxicity to DG neuronal apoptosis and memory impairment in sporadic AD (sAD) remains unclear. In this study, we established a sAD rat model through a single intraventricular injection of streptozotocin combined with intraperitoneal injection of D-galactose. We investigated the role of NR2B in DG apoptosis and spatial learning and memory by microinjecting ifenprodil, an NR2B antagonist, into the hippocampal DG. Behavioral tests showed increased escape latency, reduced swimming distance in the target quadrant and platform crossings, and the significantly increased expression of cleaved caspase-3, PARP, and p-PERK, p-eIF2α, and CHOP in the sAD rats. Microinjection of ifenprodil into the DG markedly inhibited the levels of p-PERK, p-eIF2α, CHOP, cleaved caspase-3, PARP, and neuronal apoptosis in the DG, while also ameliorating the spatial learning and memory impairments in sAD rats. These results suggest that NR2B in the hippocampal DG is associated with neuronal apoptosis via the PERK-CHOP pathway and contributes to the spatial learning and memory deficits observed in sAD rats.
海马齿状回（DG）整合多种感觉输入并编码空间记忆。在早期阿尔茨海默病（AD）中已观察到依赖DG的空间记忆缺陷。我们先前的研究表明，谷氨酸（Glu）介导的兴奋性毒性导致AD中的空间学习和记忆障碍。据报道，N-甲基-D-天冬氨酸受体（NMDAR）2B亚基（NR2B）主要定位于突触外位点，在那里它与Ca²⁺神经毒性和神经元丢失有关。然而，NR2B介导的兴奋性毒性对散发性AD（sAD）中DG神经元凋亡和记忆障碍的具体作用仍不清楚。在本研究中，我们通过脑室内单次注射链脲佐菌素并腹腔注射D-半乳糖建立了sAD大鼠模型。我们通过向海马DG微量注射NR2B拮抗剂艾芬地尔，研究了NR2B在DG凋亡以及空间学习和记忆中的作用。行为测试显示，sAD大鼠的逃避潜伏期增加、目标象限的游泳距离和平台穿越次数减少，并且裂解的半胱天冬酶-3、聚（ADP-核糖）聚合酶（PARP）以及磷酸化蛋白激酶样内质网激酶（p-PERK）、磷酸化真核起始因子2α（p-eIF2α）和C/EBP同源蛋白（CHOP）的表达显著增加。向DG微量注射艾芬地尔可显著抑制DG中p-PERK、p-eIF2α、CHOP、裂解的半胱天冬酶-3、PARP的水平以及神经元凋亡，同时还改善了sAD大鼠的空间学习和记忆障碍。这些结果表明，海马DG中的NR2B通过PERK-CHOP途径与神经元凋亡相关，并导致sAD大鼠出现空间学习和记忆缺陷。
