Sevoflurane Exposure during the Critical Period Affects Synaptic Transmission and Mitochondrial Respiration but Not Long-term Behavior in Mice

Abstract

Background Anesthesia during the synaptogenic period induces dendritic spine formation, which may affect neurodevelopment. The authors, therefore, evaluated whether changes in synaptic transmission after dendritic spine formation induced by sevoflurane were associated with long-term behavioral changes. The effects of sevoflurane on mitochondrial function were also assessed to further understand the mechanism behind spinogenesis. Methods Postnatal day 16 to 17 mice were exposed to sevoflurane (2.5% for 2 h), and synaptic transmission was measured in the medial prefrontal cortex 6 h or 5 days later. The expression of postsynaptic proteins and mitochondrial function were measured after anesthesia. Long-term behavioral changes were assessed in adult mice. Results Sevoflurane increased the expression of excitatory postsynaptic proteins in male and female mice (n = 3 to 5 per group). Sevoflurane exposure in male mice transiently increased miniature excitatory postsynaptic current frequency (control: 8.53 ± 2.87; sevoflurane: 11.09 ± 2.58) but decreased miniature inhibitory postsynaptic current frequency (control: 10.18 ± 4.66; sevoflurane: 6.88 ± 2.15). Unexpectedly, sevoflurane increased miniature inhibitory postsynaptic current frequency (control: 1.81 ± 1.11; sevoflurane: 3.56 ± 1.74) in female mice (neurons, n = 10 to 21 per group). Sevoflurane also increased mitochondrial respiration in male mice (n = 5 to 8 per group). However, such changes from anesthesia during the critical period did not induce long-term behavioral consequences. Values are presented as mean ± SD. Conclusions Sevoflurane exposure during the critical period induces mitochondrial hyperactivity and transient imbalance of excitatory/inhibitory synaptic transmission, without long-lasting behavioral consequences. Further studies are needed to confirm sexual differences and to define the role of mitochondrial activity during anesthesia-induced spine formation.

Sex differences in neurodevelopmental abnormalities caused by early-life anaesthesia exposure: a narrative review

“…Male-specific increases in cortical GABA levels in response to neonatal anaesthesia exposure would be expected to support a pattern of aberrant neuroinhibition. When GABA currents were measured in cortex after neonatal sevoflurane exposure, Chung and colleagues 13 found evidence of increased frequency of GABA-mediated miniature inhibitory postsynaptic currents. An interesting caveat is that other researchers have reported changes to neurotransmission in the absence of substantial dysregulation of molecular or cellular elements within that neurotransmitter system.…”

“…An interesting caveat is that other researchers have reported changes to neurotransmission in the absence of substantial dysregulation of molecular or cellular elements within that neurotransmitter system. For example, females exposed to anaesthesia as neonates had decreased frequency of miniature inhibitory postsynaptic currents in the cortex 13 and hippocampus 11 despite no evidence that GABA levels, receptors, or transporters were altered in these regions.…”

“…We reviewed evidence for decreased KCC2 15 and increased AMPA receptor subunits 14 in the hippocampus of anaesthesia exposed males but not females. Interestingly, despite minimal dysregulation of molecular and cellular elements of GABA neurotransmission, female rodents exposed to anaesthesia as neonates had evidence of enhanced neuroinhibition in the cortex 13 and hippocampus. 14 These findings are ripe for further exploration using electrophysiology techniques to study sex-dependent changes in neuronal excitability, synaptic transmission, and neurotransmitterereceptor systems besides glutamate and GABA.…”

The mTOR Inhibitor Rapamycin Prevents General Anesthesia-Induced Changes in Synaptic Transmission and Mitochondrial Respiration in Late Postnatal Mice

“…Previous studies also show that anesthesia-induced neurotoxicity depends on their neurodevelopmental stage. While anesthesia induces neuronal cell death in neonatal mice, the same anesthetics induces excitatory/inhibitory imbalance in late postnatal mice (Briner et al, 2010;Chung et al, 2017a;Ju et al, 2019). Importantly, excitatory/inhibitory imbalance has been linked to diverse neurodevelopmental disorders (Meredith, 2015;Lee et al, 2017).…”

Transcriptome analysis of sevoflurane exposure effects at the different brain regions

“…In this study, we focused on a simultaneous analysis of the effects of sevoflurane on the gene expression changes in multiple anatomical sites of the brain. The medial prefrontal cortex (MPFC), hippocampus, striatum, and hypothalamus were chosen as targets of the analysis, as these parts were frequently used for evaluating the effects of volatile anaesthetics [10][11][12][13]. We hypothesized that some common genes play important roles in whole brain exposed to sevoflurane and are potential regulators of the sevoflurane-induced changes in brain function.…”