Inhibition of unfolded protein response prevents post‐anesthesia neuronal hyperactivity and synapse loss in aged mice

Abstract

Delirium is the most common postoperative complication in older patients after prolonged anesthesia and surgery and is associated with accelerated cognitive decline and dementia. The neuronal pathogenesis of postoperative delirium is largely unknown. The unfolded protein response (UPR) is an adaptive reaction of cells to perturbations in endoplasmic reticulum function. Dysregulation of UPR has been implicated in a variety of diseases including Alzheimer's disease and related dementias. However, whether UPR plays a role in anesthesia-induced cognitive impairment remains unexplored. By performing in vivo calcium imaging in the mouse frontal cortex, we showed that exposure of aged mice to the inhalational anesthetic sevoflurane for 2 hours resulted in a marked elevation of neuronal activity during recovery, which lasted for at least 24 hours after the end of exposure. Concomitantly, sevoflurane anesthesia caused a prolonged increase in phosphorylation of PERK and eIF2α, the markers of UPR activation. Genetic deletion or pharmacological inhibition of PERK prevented neuronal hyperactivity and memory impairment induced by sevoflurane.Moreover, we showed that PERK suppression also reversed various molecular and synaptic changes induced by sevoflurane anesthesia, including alterations of synaptic NMDA receptors, tau protein phosphorylation, and dendritic spine loss. Together, these findings suggest that sevoflurane anesthesia causes abnormal UPR in the aged brain, which contributes to neuronal hyperactivity, synapse loss and cognitive decline

Anesthesia‐induced hippocampal‐cortical hyperactivity and tau hyperphosphorylation impair remote memory retrieval in Alzheimer's disease

“…Both of these changes favor heightened pyramidal neuron activity. These findings align with previous reports of increased pyramidal neuron activity in the prefrontal cortex of aged mice during emergence from sevoflurane anesthesia 27 . Additionally, other research groups have reported enhanced pyramidal neuronal activity following isoflurane anesthesia, which involves modulation of GABAergic boutons of PV interneurons 58 .…”

“…For example, repeated exposure of young or adult mice to sevoflurane, a commonly used inhalational anesthetic, induces tau hyperphosphorylation in the hippocampus, leading to cognitive impairment 22–26 . In aged mice, a single exposure to sevoflurane anesthesia results in a more than twofold increase in tau phosphorylation in the frontal cortex 27 . Furthermore, in patients, the incidence and severity of postoperative delirium have been linked to levels of total and phosphorylated tau in the serum, 28,29 while increased functional magnetic resonance imaging (fMRI) activity in the hippocampus of healthy older adults has shown a correlation with tau levels in cerebrospinal fluid (CSF) 30,31 .…”

CircAKT3 alleviates postoperative cognitive dysfunction by stabilizing the feedback cycle of miR-106a-5p/HDAC4/MEF2C axis in hippocampi of aged mice

“…S6E). Consistently, neuronal excitotoxicity has been confirmed to induce neuronal death after anesthesia [ 24 ]. The associated primers and fragments are shown in Table 1 .…”

Histone deacetylase 9 plays a role in sevoflurane‐induced neuronal differentiation inhibition by inactivating cAMP‐response element binding protein transcription and inhibiting the expression of neurotrophin‐3

“…In addition, only the differentiation of NSCs into neurons was studied, and the differentiation of NSCs into oligodendrocytes, for example, was not assessed. Moreover, while we utilized the sevoflurane concentrations used in our previous study, 22 clinically relevant concentrations, and those commonly used in vitro experiments, 43,44 we did not test the full range of sevoflurane concentrations. Finally, as the association of HDAC9 with CREB in neural stem cells after sevoflurane exposure is a new finding in our study, the mechanism of interaction remains to be further investigated.…”