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.

HDAC3 of dorsal hippocampus induces postoperative cognitive dysfunction in aged mice.

Postoperative cognitive dysfunction (POCD) affects a substantial number of aged individuals. Although advanced age has been regarded as the only independent risk factor for cognitive decline following anesthesia and surgery, the exact cellular and molecular mechanisms remain poorly understood. Histone deacetylase 3 (HDAC3), an epigenetic regulator of memory plays an important role in age-dependent disease. In this study, we investigated the role of HDAC3 in POCD using a laparotomy mouse model. The results showed that the level of HDAC3 in the dorsal hippocampus (DH) was elevated in aged mice compared with young mice. The surgery impaired the spatial-temporal memory in aged mice, as indicated in the object location memory (OLM) and temporal order memory (TOM) tests. Model mice also exhibited increased expression of HDAC3 protein and decreased levels of dendritic spine density and synaptic plasticity-related proteins in the DH. Selectively blocking HDAC3 in the DH of aged mice reversed spatial-temporal memory impairment induced by surgery and restored dendritic spine density and synaptic plasticity-related proteins in the DH. Overexpression of HDAC3 by adeno-associated virus in the DH of young mice mimicked the behavioral deficits induced by anesthesia and surgery. Our results indicated that HDAC3 negatively regulates spatial-temporal memory in aged mice after anesthesia and surgery. Targeting HDAC3 might represent a potential therapy to avoid POCD.