<p>Tibial fracture surgery has attracted significant interest as a notable trigger for PND. Under external stimuli such as anesthesia and surgery, the transcription factor AP-1 regulates the abnormal expression of glutamatergic neurons via interleukin-1β (IL-1β), a mechanism closely related to the pathophysiology of neurodegenerative diseases. Our research found that anesthesia and surgical exposure increased the time spent in the open arm and decreased the freezing time during context-related fear conditioning in aged mice. These effects were associated with an increase in AP-1-specific expression and elevated levels of inflammatory cytokines in glutamatergic neurons. T-5224, an inhibitor of AP-1, significantly ameliorated tibial plateau fracture (TF)-induced behavioral and memory impairment, suppressed AP-1 levels in glutamatergic neurons, reduced IL-1β expression, attenuated microglial overactivation and synaptic over-pruning, and restored neuronal structure and synaptic morphology in the hippocampus. These findings reveal that anesthesia and surgery induce impulsive-like behaviors and memory impairments in aged mice, which may be associated with inflammatory responses and synaptic loss triggered by activation of the AP-1-IL-1β pathway and overexpression of excitatory neurons in the hippocampus.</p>