Isoflurane impairs GluN2B-containing NMDA receptors trafficking and cognition via decreasing histone acetylation and EphB2 expression in aged hippocampal neurons

Perioperative neurocognitive disorders (PND) is a common complication that occurs among elderly patients in the perioperative course. Current clinical evidence has shown that isoflurane exposure could cause cognitive decline, but the exact molecular mechanisms remain unclear. As both NMDARs-dependent synaptic plasticity and histone acetylation play vital roles in processing learning and memory, we postulated that these alternations might occur in the isoflurane-associated PND. Here, we found that isoflurane impaired fear memory in aged mice, decreased GluN2B-containing NMDA receptors phosphorylation and trafficking, as well as the expression of EphB2, a key regulator of synaptic localization of NMDA receptors. We also identified that isoflurane could increase the expression of HDAC2, which was significantly enriched at the ephb2 gene promoter and regulated the transcription of ephb2. Furthermore, we showed that suberoylanilide hydroxamic acid (SAHA), a nonselective HDAC inhibitor or knocking-down HDAC2 rescued the cognitive dysfunction in isoflurane-treated aged mice via increasing acetylation of H3Ac, expression of EphB2 and promoting NMDA receptor trafficking. Collectively, our study highlighted the crucial role of histone posttranslational modifications for EphB2-GluN2B signals in isoflurane-associated PND, and modulating HDAC2 might be a new therapeutic strategy for isoflurane-associated PND.