Blocking the NR2B in the hippocampal dentate gyrus reduced the spatial memory deficits and apoptosis through the PERK-CHOP pathway in a rat model of sporadic Alzheimer's disease.

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.