Sevoflurane exposure may cause dysplasia of dendritic spines and result in fine motor dysfunction in developing mouse through the PI3K/AKT/mTOR pathway

Abstract

Sevoflurane has become one of the most widely used volatile anesthetics in pediatric surgery. However, sevoflurane exposure may interfere with dendritic development and synaptogenesis, resulting in brain function impairment. The PI3K/AKT/mTOR pathway plays an important role in dendritic development and synaptic plasticity. Here we investigated whether sevoflurane exposure would affect the morphological proportions of dendritic spines in developing mouse and explored the role of the change of plasticity of dendritic spines in sevoflurane-induced neurodevelopmental toxicity. The related signaling pathway was also examined. C57BL/6 mice at postnatal day (PND) 7 were exposed to 2% sevoflurane for 3 h. The PI3k/AKT/mTOR agonist IGF-1 or the mTOR phosphorylation inhibitor KU0063794 was intraperitoneally injected 30 min before sevoflurane or O2 exposure at PND7. Hippocampi were harvested 6 h after sevoflurane exposure. Western blotting was applied to measure the protein expression of PI3K/AKT/mTOR pathway phosphorylation. At PND14, brains from all groups were harvested for Golgi staining, and the morphology of dendritic spines of hippocampal neurons was observed by an oil immersion lens. When the mice grew to adolescence (PND48), fine motor function was measured by the Beam walking test. Here we showed that exposure to 2% sevoflurane for 3 h decreased the proportion of thin dendritic spines and increased the proportion of mushroom dendritic spines, but not changed the density of the dendritic spines. Sevoflurane exposure also suppressed the phosphorylation of the PI3K/AKT/mTOR pathway in immature mice hippocampi, and eventually led to long-term fine motor dysfunction. Meanwhile, IGF-1 pretreatment could rescue and KU0063794 pretreatment could aggravate the impairment induced by sevoflurane. In conclusion, sevoflurane exposure may cause a change of proportions of the types of dendritic spines through impacting the phosphorylation expression of the PI3K/AKT/mTOR pathway, and eventually led to long-term fine motor dysfunction in developing mouse.

Dexmedetomidine improves the circulatory dysfunction of the glymphatic system induced by sevoflurane through the PI3K/AKT/ΔFosB/AQP4 pathway in young mice

“…We simulated a model of repeated exposure to sevoflurane through in vivo and in vitro experiments. In our study, we found that the phosphorylation expression of the PI3K/AKT pathway was inhibited, which is similar to the findings of Zhong and colleagues [ 39 ]. Additionally, we discovered for the first time that the expression of ΔFosB in the hippocampal tissue of mice exposed to sevoflurane anaesthesia multiple times acutely increased.…”

The duration-dependent and sex-specific effects of neonatal sevoflurane exposure on cognitive function in rats

“…This time-dependent effect could partly avert the cognitive dysfunction caused by the neurotoxicity of sevoflurane. However, neonatal sevoflurane exposure has also been found to cause behavioral disorders, social disorders, and dysplasia in rodents, which might also be related to its unusual synaptogenesis-promoting effects ( 25 - 27 ).…”

Inhibitory neuron map of sevoflurane induced neurotoxicity model in young primates

“…Numerous studies suggest that several commonly used general anesthetics could lead to cognitive dysfunctions in adulthood (Alvarado et al, 2017;Raper et al, 2018;Zhang et al, 2022;Zhong et al, 2022). Nonetheless, the practical challenges of acquiring pediatric human brain samples necessitate the identification of suitable animal models to investigate the safety of anesthetics on brain development.…”

“…During the peak period of brain development, the abnormal morphological plasticity of dendritic spines can trigger disruptions in synapse formation, leading to long-term neurodevelopmental dysfunction Frontiers in Cellular Neuroscience 07 frontiersin.org (Bian et al, 2015). Our earlier study suggested that exposure to 2% sevoflurane for 3 h induces abnormal dendritic spine morphological proportions (but not density) and could result in abnormal neurogenesis, potentially influencing developmental brain injury (Zhong et al, 2022). Therefore, a comprehensive understanding of the SST gene's role is essential to provide a stronger foundation for fundamental research on the safety of infant brain development during anesthesia.…”