Overexpression of GluN2B Regulates Neuroinflammation through the BDNF/TrkB Signaling Pathway to Improve Postoperative Cognitive Dysfunction

Background: Postoperative cognitive dysfunction (POCD) is a common neurological complication in elderly patients. However, the mechanism by which glutamate ionotropic receptor NMDA type subunit 2B (GluN2B) contributes to POCD development remains incompletely understood. This study aimed to investigate the effects of GluN2B overexpression on POCD improvement and elucidate its underlying molecular mechanisms. Methods: In vitro, lipopolysaccharide (LPS) was used to induce inflammation in mouse primary microglia, and a microglia-HT22 neuron co-culture system was established to simulate the neurotoxic environment. Overexpression and knockdown constructs for GluN2B and brain-derived neurotrophic factor (BDNF) were generated. Western blot, ELISA, immunofluorescence, and flow cytometry were employed to assess GluN2B expression, BDNF/tropomyosin receptor kinase B (TrkB) signaling proteins, microglial M1/M2 polarization markers, neuronal apoptosis, and synaptic markers. In vivo, an aged mouse POCD model was established to evaluate the effects of GluN2B overexpression on cognitive function, neuroinflammation, and neural injury markers. Results: LPS treatment downregulated GluN2B expression in microglia (4.71-fold, p < 0.001), promoted polarization toward the pro-inflammatory M1 phenotype, and suppressed the BDNF/TrkB pathway. GluN2B overexpression significantly reversed these effects by inhibiting M1 polarization, enhancing anti-inflammatory M2 polarization, and activating BDNF/TrkB signaling. In the microglia-HT22 co-culture system, GluN2B overexpression markedly attenuated LPS-activated microglia-induced neuronal apoptosis (1.74-fold, p < 0.001), intracellular Ca2+ overload (1.94-fold, p < 0.001), and synaptic protein loss in HT22 cells, whereas BDNF knockdown abolished these protective effects. In the aged POCD mouse model, GluN2B overexpression improved learning and memory performance and reduced neuronal apoptosis (1.92-fold, p < 0.001) and histopathological damage in the prefrontal cortex. Conclusion: This study demonstrates that GluN2B overexpression activates the BDNF/TrkB pathway to reduce neuroinflammation, protect neurons and synapses, and ameliorate POCD symptoms in aged mice, providing a potential therapeutic target for POCD management.